Heteroaryl amide compounds as sting activators

ABSTRACT

The present application provides heteroaryl amide compounds that activate the STING pathway to produce interferons, which are useful in the treatment of various diseases including infectious diseases and cancer.

TECHNICAL FIELD

The present application provides heteroaryl amide compounds thatactivate the STING pathway to produce interferons, which are useful inthe treatment of various diseases including infectious diseases andcancer.

BACKGROUND

The innate immunity is the first line of defense against infection fromforeign microorganisms including bacteria, viruses, parasites and otherinfectious threats, but it also responds to certain danger signalsassociated with cellular or tissue damage. This response is initiated byactivation of so-called pattern recognition receptors that can detectdifferent forms of foreign antigens, i.e. nucleic acids, peptides,carbohydrates, and more, which then lead to production of interferons,proinflammatory chemokines and cytokines, and anti-microbial peptides tofight infection (Palm and Medzhitov, Immunol Rev (2009) 227:221-233;Takeuchi and Akira, Immunol Rev (2009) 227:75-86; Beutler, Blood (2009)113:1399-1407). STING (stimulator of interferon genes), also known asMITA, MPYS, ERIS, and TMEM173, is one of such pattern recognitionreceptors in the innate immune response that could detect cytosolicnucleic acids (Ishikawa and Barber, Nature (2008) 455:674-678). Directbinding of STING to its ligands induces a conformational change of thecomplex resulting in a downstream signaling cascade involving TBK1activation, IRF-3 phosphorylation, and production of type I IFNs andother proinflammatory cytokines, such as TNF, IL-6 and IFNγ (Ishikawaand Barber, Nature (2008) 455:674-678).

Type I interferons play a central role in orchestrating host anti-viralresponse through inhibiting viral replication in infected cells,activating and enhancing antigen presentation and triggering theadaptive immune response through direct and indirect action on T and Bcells (McNab et al, Nat Rev Immunol (2015) 15:87-103; Crosse et al, JInnate Immun (2018) 10:85-93). Therefore, this cytokine acts as a masterregulator whose induction in the early stages of viral infectionmodulates downstream signaling cascades that promote bothproinflammatory and anti-inflammatory responses. Thus type I IFNs havebeen evaluated as a therapeutic agent for chronic viral infection suchas HCV and HIV (Enomoto and Nishiguchi, World J Hepatol (2015)7:2681-2687; Azzoni et al, J Infect Dis (2013) 207:213-222; Lane et al,Ann Intern Med (1990) 112:805-11).

The use of type I interferons (IFNs) (the IFNα family and IFNβ) aspotential antitumor agents has also been investigated (Kirkwood, SeminOncol (2002) 29:18-26; Tarhini et al, J Immunol (2012) 189:3789-3793).IFNs have multiple anticancer mechanisms that include: direct inhibitionon tumor cell proliferation and angiogenesis; induction oftumor-specific cytotoxic T-cells; plus other immunoregulatory effects onantibody production, natural killer (NK) cell activation, macrophagefunction, delayed-type hypersensitivity, and major histocompatibilitycomplex antigen expression (Hervas-Stubbs et al, Clin Cancer Res (2011)17:2619-2627; Vannucchi et al, Curr Med Chem (2007) 14:667-679).Anticancer activity of type I IFNs has been demonstrated in patientswith hematological malignancies (e.g., hairy cell leukemia) and solidtumors (e.g., renal cell carcinoma and malignant melanoma) (Quesada etal, N Engl J Med (1984) 310:15-18; Pizzocaro et al, J Clin Oncol (2001)19:425-431; Garbe and Eigentler, Melanoma Res (2007) 17:117-127),however, the results and overall efficacy have been modest. This may bedue to intrinsic resistance to IFN-induced ceil death, to tire shorthalf-life (˜30 minutes) of intravenously or subcutaneously dosed IFN, todose-limiting systemic tenacities, and/or to the development ofneutralizing antibodies against recombinant IFN protein. Urns, thedevelopment of an agent tike a STING agonist to induce production oftype I interferons will be of interest to the field. Currently, thereare two different classes of STING agonists: cyclic dinucleotide andsmall molecule.

Cyclic dinucleotides (CDNs) can directly bind and activate STING, andthe complex of bacterial CDN and STING has been confirmed by X-raycrystallography recently (Burdette and Vance, Nat Immunol (2013)14:19-26). In mammalian cells, the primary sensor of cyclic doublestranded DNA (dsDNA), namely cyclic GMP-AMP synthetase (cGAS), canconvert those cyclic dsDNA into a mammalian CDN cGAMP (cyclic guanosinemonophosphate-adenosine monophosphate; Gao et al, Cell (2013)154:748-762). The interaction of cGAMP and STING has also been confirmedby X-ray crystallography (Cai et al, Mol Cell (2014) 54:289-296).Synthetic derivatives of cGAMP have been synthesized and showedexcellent cellular potency to activate both mouse and human STING invitro, as well as demonstrated good anti-tumor efficacy in preclinicalmouse models (Corrales et al, Cell Rep (2015) 11:1018-1030).

Small molecules that can activate STING have also been identified, DMXAA(5,6-dimethylxanthenone-4-acetic acid) and CMA(10-carboxymethyl-9-acridanone) (Perera et al, J Immunol (1994)153:4684-4697; Kramer et al, Antimicrob Agents Chemother (1976)9:233-238). These two chemically-unrelated compounds can activate theSTING pathway, and block multiple viruses from replication (Guo et al,Agents Chemother (2015) 59:1273-1281; Cheng et al, Am J Respir Cell MolBiol (2011) 45:480-488). Intriguingly, DMXAA demonstrates excellentanti-tumor activity in preclinical mouse models by priming CD8+ T cellsresponses to promote rejection of established tumors in aSTING-dependent manner, inducing tumor necrosis through disruption oftumor vasculature, as well as augmenting cancer vaccine effect (Corraleset al, Cell Rep (2015) 11:1018-1030; Wallace et al, Cancer Res (2007)67:7011-7019; Tang et al, Flos One (2013) 8:1-6). Unfortunately, bothDMXAA and CMA were found to only bind and activate mouse STING, but nothuman STING (Caviar et al, EMBO J(2013) 32:1440-1450; Kim et al, ACSChem Biol (2013) 8:1396-1401).

Hence, there is a need to develop small molecule entities that canactivate human STING and induce upregulation of IRF3 and NFκB pathway,which can later lead to production of interferons and otherproinflammatory cytokines and chemokines. This type of immunomodulatingagents may be useful not only in infectious disease to activate innateimmunity, but also in cancer, and as vaccine adjuvants. This applicationis directed to this need and others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of activating STING,comprising contacting the receptor with a compound of Formula (I), or apharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION Compounds

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

r is 0, 1, 2, 3, or 4;

u is 0, 1, 2, 3, or 4;

v is 0, 1, 2, 3, or 4;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, then R¹ and R^(1″) are each a bond;

when n is 0, then R¹ and R^(1″) are each independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋m aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(1A) substituents;

each R^(1A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a1), SR^(a1), NHOR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)NR^(c1)(OR^(a1)), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))R^(b1), NR^(c1)S(O)NR^(c1)R^(d1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)(═NR^(e1))R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), OS(O)(═NR^(e1))R^(b1), OS(O)₂R^(b1), SF₅,P(O)R^(f1)R^(g1), OP(O)(OR^(h1))(OR^(i1)), P(O)(OR^(h1))(OR^(i1)), andBR^(j1)R^(k1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(1B) substituents;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl,C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(1B) substituents;

or, any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-14 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-14 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(1B)substituents;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(1B) substituents;

each R^(e1) is independently selected from H, OH, CN, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f1) and R^(g1) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h1) and R^(i1) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j1) and R^(k1) is independently selected from OH, C₁₋₆alkoxy,and C₁₋₆haloalkoxy;

or any R^(j1) and R^(k1) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl:

each R^(1B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a11), SR^(a11), NHOR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11),C(O)NR^(c11)(OR^(a11)), C(O)OR^(a11), OC(O)R^(b11),OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)NR^(c11)R^(d11),NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11), NR^(c11)C(O)NR^(c11)R^(d11),C(═NR^(e11))R^(b11), C(═NR^(e11))NR^(c11)R^(d11),NR^(c11)C(═NR^(e11))NR^(c11)R^(d11), NR^(c11)C(═NR^(e11))R^(b11),NR^(c11)S(O)NR^(c11)R^(d11), NR^(c11)S(O)R^(b11), NR^(c11)S(O)₂R^(b11),NR^(c11)S(O)(═NR^(e11))R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),S(O)R^(b11), S(O)NR^(c11)R^(d11), S(O)₂R^(M1), S(O)₂NR^(c11)R^(d11),OS(O)(═NR^(e11))R^(b11), OS(O)₂R^(b11), SF₅, P(O)R^(f11)R^(g11),OP(O)(OR^(h11))(OR^(i11)), P(O)(OR^(h11))(OR^(i11)), andBR^(j11)R^(k11), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents;

each R^(a11), R^(c11), and R^(d11) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(S) substituents;

or, any R^(c11) and R^(d11) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(S) substituents;

each R^(e11) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f11) and R^(g11) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h11) and R^(i11) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j11) and R^(k11) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j11) and R^(k11) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R², R³, R⁶, R⁷, R⁸ and each R⁴ are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), NHOR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2),NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))R^(b2),NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)(═NR^(e2))R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2),OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅, P(O)R^(f2)R^(g2),OP(O)(OR^(h2))(OR^(i2)), P(O)(OR^(h2))(OR^(i2)), and BR^(j2)R^(k2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

when s is 1, then R⁵ is a bond;

when s is 0, then R⁵ is independently selected from H, D, halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a2), SR^(a2), NHOR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))R^(b2), NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)(═NR^(e2))R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅,P(O)R^(f2)R^(g2), OP(O)(OR^(h2))(OR^(i2)), P(O)(OR^(h2))(OR^(i2)), andBR^(j2)R^(k2), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

or, any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-14 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-14 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents; each R^(b2) is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents;

each R^(e2) is independently selected from H, OH, CN, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl;

each R^(f2) and R^(g2) are independently selected from H, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl;

each R^(h2) and R^(i2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(j2) and R^(k2) is independently selected from OH, C₁₋₆alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j2) and R^(k2) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(2A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))R^(b21),NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)(═NR^(e21))R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21),S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), OS(O)₂R^(b21), SF₅, P(O)R^(f21)R^(g21),OP(O)(OR^(h21))(OR^(i21)), P(O)(OR^(h21))(OR^(i21)), andBR^(j21)R^(k21), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents;

or, any R^(c21) and R^(d21) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(2B)substituents;

each R^(b21) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2B) substituents;

each R^(e21) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f21) and R^(g21) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h21) and R^(i21) is independently selected from H, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j21) and R^(k21) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j21) and R^(k21) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl:

each R^(2B) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a22), SR^(a22), NHOR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22),C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═NR^(e22))R^(b22), C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))R^(b22),NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), OS(O)₂R^(b22), SF₅, P(O)R^(f22)R^(g22),OP(O)(OR^(h22))(OR^(i22)), P(O)(OR^(h22))(OR^(i22)), andBR^(j22)R^(k22), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents;

each R^(a22), R^(c22), and R^(d22) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(S) substituents;

or, any R^(c22) and R^(d22) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each R^(b22) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(S) substituents;

each R^(e22) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f22) and R^(g22) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h22) and R^(i22) is independently selected from H, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j22) and R^(k22) is independently selected from OH, C₁₋₆alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j22) and R^(k22) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

U is N or CR^(U);

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein (i) Z is CR^(Z), U is CR^(U), and Y is CR^(Y); or (ii) Z is N, Uis CR^(U), and Y is CR^(Y); or (iii) Z is CR^(Z), U is N, and Y isCR^(Y); or (iv) Z is CR^(Z), U is CR^(U), and Y is N; or (v) Z is N, Uis N, and Y is CR^(Y); or (vi) Z is CR^(Z), U is N, and Y is N; or (vii)Z is N, U is CR^(U), and Y is N; R^(U), R^(Y), and R^(Z) are eachindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a0), SR^(a0), NHOR^(a0), C(O)R^(b0), C(O)NR^(c0)R^(d0),C(O)NR^(c0)(OR^(a0)), C(O)OR^(a0), OC(O)R^(b0), OC(O)NR^(c0)R^(d0),NR^(c0)R^(d0) NR^(c0)NR^(c0)R^(d0), NR^(c0)C(O)R^(b0),NR^(c0)C(O)OR^(a0), NR^(c0)C(O)NR^(c0)R^(d0), C(═NR^(e0))R^(b0),C(═NR^(e0))NR^(c0)R^(d0), NR^(c0)C(═NR^(e0))NR^(c0)R^(d0),NR^(c0)C(═NR^(e0))R^(b0), NR^(c0)S(O)NR^(c0)R^(d0), NR^(c0)S(O)R^(b0),NR^(c0)S(O)₂R^(b0), NR^(c0)S(O)(═NR^(e0))R^(b0),NR^(c0)S(O)₂NR^(c0)R^(d0), S(O)R^(b0), S(O)NR^(c0)R^(d0), S(O)₂R^(b0),S(O)₂NR^(c0)R^(d0), OS(O)(═NR^(e0))R^(b0), OS(O)₂R^(b0), SF₅,P(O)R^(f0)R^(g0), OP(O)(OR^(h0))(OR^(i0)), P(O)(OR^(h0))(OR^(i0)), andBR^(j0)R^(k0), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents;

or, any R^(c0) and R^(d0) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-14 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-14 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each R^(b0) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, which are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each R^(e0) is independently selected from H, OH, CN, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl;

each R^(f0) and R^(g0) are independently selected from H, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl;

each R^(h0) and R^(i0) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(j0) and R^(k0) is independently selected from OH, C₁₋₆alkoxy,and C₁₋₆ haloalkoxy:

or any R^(j0) and R^(k0) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl:

Ring moiety A is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl;

Ring moiety B is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl;

Ring C is selected from a phenyl ring, a 5-6 membered heteroaryl ring, aC₃₋₇ cycloalkyl ring, and a 5-7 membered heterocycloalkyl ring;

each R^(A) and R^(B) is independently selected from H, D, halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a9), SR^(a9), NHOR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9),C(O)NR^(c9)(OR^(a9)), C(O)OR^(a9), OC(O)R^(b9), OC(O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), C(═NR^(e9))R^(b9),C(═NR^(e9))NR^(c9)R^(d9), NR^(c9)C(═NR^(e9))NR^(c9)R^(d9),NR^(c9)C(═NR^(e9))R^(b9), NR^(c9)S(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)(═NR^(e9))R^(b9),NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9), S(O)NR^(c9)R^(d9), S(O)₂R^(b9),S(O)₂NR^(c9)R^(d9), OS(O)(═NR^(e9))R^(b9), OS(O)₂R^(b9), SF₅,P(O)R^(f9)R^(g9), P(O)(OR^(h9))(OR^(i9)), P(O)(OR^(h9))(OR^(i9)), andBR^(j9)R^(k9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents;

or, any R^(c9) and R^(d9) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-14 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-14 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(9A)substituents;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, which are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(9A)substituents;

each R^(e9) is independently selected from H, OH, CN, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl;

each R^(f9) and R^(g9) are independently selected from H, C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl;

each R^(h9) and R^(i9) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;

each R^(j9) and R^(k9) is independently selected from OH, C₁₋₆alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j9) and R^(k9) attached to the same B atom, together with theB atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl:

each R^(9A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a91), SR^(a91), NHOR^(a91), C(O)R^(b91), C(O)NR^(c91)R^(d91),C(O)NR^(c91)(OR^(a91)), C(O)OR^(a91), OC(O)R^(b91),OC(O)NR^(c91)R^(d91), NR^(c91)R^(d91), NR^(c91)NR^(c91)R^(d91),NR^(c91)C(O)R^(b91), NR^(c91)C(O)OR^(a91), NR^(c91)C(O)NR^(c91)R^(d91),C(═NR^(e91))R^(b91), C(═NR^(e91))NR^(c91)R^(d91),NR^(c91)C(═NR^(e91))NR^(c91)R^(d91), NR^(c91)C(═NR^(e91))R^(b91),NR^(c91)S(O)NR^(c91)R^(d91), NR^(c91)S(O)R^(b91), NR^(c91)S(O)₂R^(b91),NR^(c91)S(O)(═NR^(e91))R^(b91), NR^(c91)S(O)₂NR^(c91)R^(d91),S(O)R^(b91), S(O)NR^(c91)R^(d91), S(O)₂R^(b91), S(O)₂NR^(c91)R^(d91),OS(O)(═NR^(e91))R^(b91), OS(O)₂R^(b91), SF₅, P(O)R^(B1)R^(g91),OP(O)(OR^(h91))(OR^(i91)), P(O)(OR^(h91))(OR^(i91)), andBR^(j91)R^(k91), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents;

each R^(a91), R^(c91), and R^(d91) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(S) substituents;

or, any R^(c91) and R^(d91) attached to the same N atom, together withthe N atom to which they are attached, form a 5- or 6-memberedheteroaryl or a 4-7 membered heterocycloalkyl group, wherein the 5- or6-membered heteroaryl or 4-7 membered heterocycloalkyl group isoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each R^(b91) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(S) substituents;

each R^(e91) is independently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(f91) and R^(g91) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl;

each R^(h91) and R^(i91) is independently selected from H, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(j91) and R^(k91) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy;

or any R^(j91) and R^(k91) attached to the same B atom, together withthe B atom to which they are attached, form a 5- or 6-memberedheterocycloalkyl group optionally substituted with 1, 2, 3, or 4substituents independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl:

L¹, L², and L³ are each independently selected from —R—R—, —R—R—R—,-Cy-, —R-Cy-, -Cy-R—, —R-Cy-R—, —R—R-Cy-, -Cy-R—R—, and -Cy-R-Cy-;provided that when L² is present, then L² is ortho to the bondconnecting Ring moiety A to the —NR²—C(═O)— moiety, and L² is ortho tothe bond connecting Ring moiety B to UYZ ring;

each R is independently selected from M, C₁₋₆ alkylene, C₂₋₆ alkenylene,C₂₋₆ alkynylene, C₁₋₆ alkylene-M, M-C₁₋₆ alkylene, C₁₋₆ alkylene-M-C₁₋₆alkylene, M-C₁₋₆ alkylene-M, C₂₋₆ alkenylene-M, M-C₂₋₆ alkenylene, C₂₋₆alkenylene-M-C₂₋₆ alkenylene, M-C₂₋₆ alkenylene-M, C₂₋₆ alkynylene-M,M-C₂₋₆ alkynylene, C₂₋₆ alkynylene-M-C₂₋₆ alkynylene, and M-C₂₋₆alkynylene-M, wherein each of said C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene is optionally substituted with 1, 2, 3, or 4substituents independently selected R^(S) substituents;

each Cy is independently selected from C₃₋₁₄ cycloalkyl, phenyl, 4-14membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each M is independently selected from —O—, —S—, —C(O)—, —C(O)NR^(L)—,—C(O)O—, —OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂—, —S(O)₂—, —S(O)₂NR^(L)—, and—NR^(L)S(O)₂NR^(L)—; provided that when M is attached to a nitrogenatom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—,and —S(O)₂NR^(L)—;

each R^(L) is independently selected from H, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, and C₁₋₃ haloalkyl; and

each R^(S) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, Ring C is a 5-6 membered heteroaryl ring or a 5-7membered heterocycloalkyl ring. In some embodiments, Ring C is a5-membered heteroaryl ring or a 6-membered heterocycloalkyl ring. Insome embodiments, Ring C is a 5-membered heteroaryl ring. In someembodiments, Ring C is furanyl or thienyl. In some embodiments, Ring Cis furanyl.

In some embodiments, Ring moiety A is selected from monocyclic C₃₋₇cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, andmonocyclic 5-6 membered heteroaryl.

In some embodiments, Ring moiety A is 5-6 membered heteroaryl.

In some embodiments, Ring moiety A is 5-membered heteroaryl.

In some embodiments, Ring moiety A is a pyrazole ring.

In some embodiments, Ring moiety B is selected from monocyclic C₃₋₇cycloalkyl, phenyl, monocyclic 4-7 membered heterocycloalkyl, andmonocyclic 5-6 membered heteroaryl.

In some embodiments, Ring moiety B is 5-6 membered heteroaryl.

In some embodiments, Ring moiety B is 5-membered heteroaryl.

In some embodiments, Ring moiety B is a pyrazole ring.

In some embodiments, each R^(A) is independently selected from H, halo,CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(A) is independently selected from H andC₁₋₆ alkyl.

In some embodiments, each R^(A) is independently selected from H,methyl, and ethyl.

In some embodiments, each R^(B) is independently selected from H, halo,CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(B) is independently selected from H andC₁₋₆ alkyl.

In some embodiments, each R^(B) is independently selected from H,methyl, and ethyl.

In some embodiments, r is 0.

In some embodiments, r is 1.

In some embodiments, r is 2.

In some embodiments, r is 3.

In some embodiments, r is 4.

In some embodiments, r is 0, 1, or 2.

In some embodiments, u is 0.

In some embodiments, u is 1.

In some embodiments, u is 2.

In some embodiments, u is 3.

In some embodiments, u is 4.

In some embodiments, u is 0, 1, or 2.

In some embodiments, v is 0.

In some embodiments, v is 1.

In some embodiments, v is 2.

In some embodiments, v is 3.

In some embodiments, v is 4.

In some embodiments, v is 0, 1, or 2.

In some embodiments, r is 0, 1, or 2; u is 0, 1, or 2; and v is 0, 1, or2.

In some embodiments, r is 0; u is 0, 1, or 2; and v is 0, 1, or 2.

In some embodiments, R², R³, R⁶, R⁷, R⁸ and each R⁴ are eachindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), and OP(O)(OR^(h2))(OR^(i2)), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

when s is 1, then R⁵ is a bond;

when s is 0, then R⁵ is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), and OP(O)(OR^(h2))(OR^(i2)), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

or, any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2A) substituents;

each R^(h2) and R^(i2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(2A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a21), SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)₂R^(b21),S(O)₂NR^(c21)R^(d21), and OP(O)(OR^(h21))(OR^(i21)), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆haloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

each R^(b21) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

each R^(h21) and R^(i21) is independently selected from H and C₁₋₆alkyl; and

each R^(2B) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, R², R³, R⁶, R⁷, R⁸ and each R⁴ are eachindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents;

when s is 1, then R⁵ is a bond;

when s is 0, R⁵ is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

or, any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2A) substituents; and

each R^(2A) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, R², R³, R⁶, R⁷, R⁸ and each R⁴ are eachindependently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, OR^(a2), SR³², C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

when s is 1, then R⁵ is a bond;

when s is 0, R⁵ is selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents; and

each R^(2A) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, R², R³, R⁶, R⁷, R⁸ and each R⁴ are eachindependently selected from H, D, halo, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C(O)NR^(c2)R^(d2), and OR^(a2);

when s is 1, then R⁵ is a bond;

when s is 0, then R⁵ is selected from H, D, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C(O)NR^(c2)R^(d2), and OR^(a2);

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; and

each R^(2A) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, R², R³, R⁶, R⁷, R⁸ and each R⁴ are eachindependently selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)NR^(c2)R^(d2), and OR^(a2);

when s is 1, then R⁵ is a bond; and

when s is 0, then R⁵ is selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C(O)NR^(c2)R^(d2), and OR^(a2).

In some embodiments, R², R³, R⁶, R⁷, R⁸ and each R⁴ are eachindependently selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)NH₂, OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy;

when s is 1, then R⁵ is a bond; and

when s is 0, then R⁵ is selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C(O)NH₂, OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy.

In some embodiments, each R^(a2), R^(c2), and R^(d2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; and

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents.

In some embodiments, each R^(2A) is independently selected from H, D,OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl,carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxy carbonyl, C₁₋₃alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino,C₁₋₃ alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.

In some embodiments, each R^(2A) is independently selected from HO—C₁₋₃alkyl and C₁₋₃ alkoxy-C₁₋₃ alkyl.

In some embodiments, R², R³, R⁵, R⁶, R⁷, R⁸ and each R⁴ are eachindependently selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)NH₂, OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, wherein the C₁₋₆ alkoxyis optionally substituted by HO—C₁₋₃ alkyl or C₁₋₃ alkoxy-C₁₋₃ alkyl.

In some embodiments, R² is selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, wherein the C₁₋₆alkoxy is optionally substituted by HO—C₁₋₃ alkyl or C₁₋₃ alkoxy-C₁₋₃alkyl.

In some embodiments, R² is H.

In some embodiments, R³ is selected from C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); and each R^(a2),R^(b2), R^(c2), and R^(d2) is independently selected from H and C₁₋₆alkyl. In some embodiments, R³ is C(O)NH₂.

In some embodiments, each R⁴ is independently selected from H, D, halo,CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy,wherein the C₁₋₆ alkoxy is optionally substituted by HO—C₁₋₃ alkyl orC₁₋₃ alkoxy-C₁₋₃ alkyl.

In some embodiments, each R⁴ is H.

In some embodiments, R⁵ is selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, wherein the C₁₋₆alkoxy is optionally substituted by HO—C₁₋₃ alkyl or C₁₋₃ alkoxy-C₁₋₃alkyl.

In some embodiments, R⁵ is selected from methoxy, 3-hydroxypropoxy, and3-methoxypropoxy.

In some embodiments, R⁶ is selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, wherein the C₁₋₆alkoxy is optionally substituted by HO—C₁₋₃ alkyl or C₁₋₃ alkoxy-C₁₋₃alkyl.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is selected from C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); and each R^(a2),R^(b2), R^(c2), and R^(d2) is independently selected from H and C₁₋₆alkyl.

In some embodiments, R⁷ is C(O)NH₂.

In some embodiments, R⁸ is selected from H, D, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, wherein the C₁₋₆alkoxy is optionally substituted by HO—C₁₋₃ alkyl or C₁₋₃ alkoxy-C₁₋₃alkyl.

In some embodiments, R⁸ is H.

In some embodiments, R², R⁶, R⁸, and each R⁴ are each H.

In some embodiments, R³ and R⁷ are each C(O)NH₂.

In some embodiments, R², R⁶, R⁸, and each R⁴ are each H, and R³ and R⁷are each C(O)NH₂.

In some embodiments, when n is 1, then R¹ and R^(1″) are each a bond;

when n is 0, then R¹ and R^(1″) are each independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(1A) substituents; and

each R^(1A) is independently selected from H, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, when n is 1, then R¹ and R^(1″) are each a bond;and

when n is 0, then R¹ and R^(1″) are each independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, and cyclopropyl.

In some embodiments, when n is 1, then R¹ and R^(1″) are each a bond;and

when n is 0, then R¹ and R^(1″) are each independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, Z is CR^(Z), U is CR^(U), and Y is CR^(Y).

In some embodiments, Z is N, U is CR^(U), and Y is CR^(Y).

In some embodiments, Z is CR^(Z), U is N, and Y is CR^(Y).

In some embodiments, Z is CR^(Z), U is CR^(U), and Y is N.

In some embodiments, Z is N, U is N, and Y is CR^(Y).

In some embodiments, Z is CR^(Z), U is N, and Y is N.

In some embodiments, Z is N, U is CR^(U), and Y is N.

In some embodiments, Z is N, U is CH, and Y is N.

In some embodiments, R^(U), R^(Y), and R^(Z) are each independentlyselected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, OR^(a0), SR^(a0), NHOR^(a0), C(O)R^(b0),C(O)NR^(c0)R^(d0), C(O)NR^(c0)(OR^(a0)), C(O)OR^(a0), OC(O)R^(b0),OC(O)NR^(c0)R^(d0), NR^(c0)R^(d0), NR^(c0)NR^(c0)R^(d0),NR^(c0)C(O)R^(b0), NR^(c0)C(O)OR^(a0), NR^(c0)C(O)NR^(c0)R^(d0),NR^(c0)S(O)₂R^(b0), NR^(c0)S(O)₂NR^(c0)R^(d0), S(O)₂R^(b0),S(O)₂NR^(c0)R^(d0), and OP(O)(OR^(h0))(OR^(i0)), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆ haloalkylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(S) substituents;

each R^(b0) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents; and each R^(h0) and R^(i0) isindependently selected from H and C₁₋₆ alkyl.

In some embodiments, R^(U), R^(Y), and R^(Z) are each independentlyselected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, C₁₋₃ alkyl,C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkyl,C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, and C₁₋₃ alkoxycarbonyl.

In some embodiments, R^(U), R^(Y), and R^(Z) are each independentlyselected from H, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(U), R^(Y), and R^(Z) are each independentlyselected from H and C₁₋₆ alkyl.

In some embodiments, R^(U), R^(Y), and R^(Z) are each H.

In some embodiments, L¹, L², and L³ are each independently selected from—R—R—, —R—R—R—, -Cy-, —R-Cy-, -Cy-R—, and —R-Cy-R—.

In some embodiments, L¹, L², and L³ are each independently selected from—R—R—, —R—R—R—, -Cy-, —R-Cy-, and -Cy-R—.

In some embodiments, L¹, L², and L³ are each independently selected from—R—R— and —R—R—R—.

In some embodiments, L¹ is —R—R—R—.

In some embodiments, L¹ is —R—R—.

In some embodiments, L² is —R—R—R—.

In some embodiments, L² is —R—R—.

In some embodiments, L³ is —R—R—R—.

In some embodiments, L³ is —R—R—.

In some embodiments, each R is independently selected from M, C₁₋₆alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₁₋₆ alkylene-M, and M-C₁₋₆alkylene, wherein said C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆alkynylene are optionally substituted with 1, 2, 3, or 4 substituentsindependently selected R^(S) substituents.

In some embodiments, each R is independently selected from M, C₁₋₆alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene.

In some embodiments, each R is independently selected from M, C₁₋₃alkylene, C₂₋₃ alkenylene, and C₂₋₃ alkynylene.

In some embodiments, each R is independently selected from C₁₋₆ alkyleneand C₂₋₆ alkenylene.

In some embodiments, each R is independently selected from C₁₋₃ alkyleneand C₂₋₃ alkenylene.

In some embodiments, each M is independently selected from —O—, —C(O)—,—C(O)NR^(L)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)S(O)₂—, —S(O)₂—, and —S(O)₂NR^(L)—, provided that when M isattached to a nitrogen atom, then M is selected from —C(O)—,—C(O)NR^(L)—, —C(O)O—, —S(O)₂—, and —S(O)₂NR^(L)—; and each R^(L) isindependently selected from H and C₁₋₃ alkyl.

In some embodiments, each M is independently selected from —O—, —C(O)—,—C(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂—,—S(O)₂—, and —S(O)₂NR^(L)—, provided that when M is attached to anitrogen atom, then M is selected from —C(O)—, —C(O)NR^(L)—, —S(O)₂—,and —S(O)₂NR^(L)—; and each R^(L) is independently selected from H andC₁₋₃ alkyl.

In some embodiments, each Cy is independently selected from C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents.

In some embodiments, L¹ is —CH₂—CH═CH—CH₂—.

In some embodiments, L² is —CH₂—CH═CH—CH₂—.

In some embodiments, L³ is —CH₂—CH═CH—CH₂—.

In one embodiment (a):

r is 0, 1, 2, 3, or 4;

u is 0, 1, 2, 3, or 4;

v is 0, 1, 2, 3, or 4;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, then R¹ and R^(1″) are each a bond;

when n is 0, then R¹ and R^(1′) are each independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl,C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(1A) substituents;

each R^(1A) is independently selected from H, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

R², R³, R⁶, R⁷, R⁸ and each R⁴ are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR³², SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), andOP(O)(OR^(h2))(OR^(i2)), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CM haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(2A) substituents;

when s is 1, then R⁵ is a bond;

when s is 0, then R⁵ is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), and OP(O)(OR^(h2))(OR^(i2)), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

or, any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2A) substituents;

each R^(h2) and R^(i2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl;

each R^(2A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a21), SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)₂R^(b21),S(O)₂NR^(c21)R^(d21), and OP(O)(OR^(h21))(OR^(i21)), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents;

each R^(a21), R^(c21), and R^(d21) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆haloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

each R^(b21) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

each R^(h21) and R^(i21) is independently selected from H and C₁₋₆alkyl;

each R^(2B) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

U is N or CR^(U);

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein (i) Z is CR^(Z), U is CR^(U), and Y is CR^(Y); or (ii) Z is N, Uis CR^(U), and Y is CR^(Y); or (iii) Z is CR^(Z), U is N, and Y isCR^(Y); or (iv) Z is CR^(Z), U is CR^(U), and Y is N; or (v) Z is N, Uis N, and Y is CR^(Y); or (vi) Z is CR^(Z), U is N, and Y is N; or (vii)Z is N, U is CR^(U), and Y is N;

R^(X), R^(Y), and R^(Z) are each independently selected from H, D, halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a0), SR^(a0), NHOR^(a0), C(O)R^(b0), C(O)NR^(c0)R^(d0),C(O)NR^(c0)(OR^(a0)), C(O)OR^(a0), OC(O)R^(b0), OC(O)NR^(c0)R^(d0),NR^(c0)R^(d0), NR^(c0)NR^(c0)R^(d0), NR^(c0)C(O)R^(b0),NR^(c0)C(O)OR^(a0), NR^(c0)C(O)NR^(c0)R^(d0), NR^(c0)S(O)₂R^(b0),NR^(c0)S(O)₂NR^(c0)R^(d0), S(O)₂R^(b0), S(O)₂NR^(c0)R^(d0), andOP(O)(OR^(h0))(OR^(i0)), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl are each optionally substituted with 1, 2,3, or 4 independently selected R^(S) substituents;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆ haloalkylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(S) substituents;

each R^(b0) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, which are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents;

each R^(h0) and R^(i0) is independently selected from H and C₁₋₆ alkyl;

Ring moiety A is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl;

Ring moiety B is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl;

Ring C is selected from a phenyl ring, a 5-6 membered heteroaryl ring, aC₃₋₇ cycloalkyl ring, and a 5-7 membered heterocycloalkyl ring;

each R^(A) and R^(B) is independently selected from H, halo, CN, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(A) and R^(B) is independently selected from H, halo, CN, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

L¹, L², and L³ are each independently selected from —R—R—, —R—R—R—,-Cy-, —R-Cy-, -Cy-R—, and —R-Cy-R—;

R is independently selected from M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, and M-C₁₋₆ alkylene, wherein each of saidC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected R^(S)substituents;

each Cy is independently selected from C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents;

each M is independently selected from —O—, —C(O)—, —C(O)NR^(L)—,—NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂—, —S(O)₂—, and—S(O)₂NR^(L)—, provided that when M is attached to a nitrogen atom, thenM is selected from —C(O)—, —C(O)NR^(L)—, —S(O)₂—, and —S(O)₂NR^(L)—;

each R^(L) is independently selected from H and C₁₋₃ alkyl; and

each R^(S) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In one embodiment (b):

r is 0, 1, 2, 3, or 4;

u is 0, 1, 2, 3, or 4;

v is 0, 1, 2, 3, or 4;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, then R¹ and R^(1″) are each a bond;

when n is 0, then R¹ and R^(1″) are each independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆alkyl, HO-CM, alkyl, and C₁₋₆ alkoxy-C₁₋₆ alkyl;

R², R³, R⁶, R⁷, R⁸ and each R⁴ are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl,OR³², SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

when s is 1, then R⁵ is a bond;

when s is 0, then R⁵ is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl,C₃₋₇cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl,C₃₋₇cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

or, any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 5- or 6-membered heteroaryl ora 4-7 membered heterocycloalkyl group, wherein the 5- or 6-memberedheteroaryl or 4-7 membered heterocycloalkyl group is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, which are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2A) substituents;

each R^(2A) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

U is CR^(U);

Y is N;

Z is N;

R^(U) is selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, and C₁₋₃ alkoxycarbonyl;

Ring moiety A is 5-6 membered heteroaryl;

Ring moiety B is 5-6 membered heteroaryl;

Ring C is a 5-6 membered heteroaryl ring;

each R^(A) and R^(B) is independently selected from H, halo, CN, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(A) and R^(B) is independently selected from H, halo, CN, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

L¹, L², and L³ are each independently selected from —R—R— and —R—R—R—

R is independently selected from M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, and M-C₁₋₆ alkylene, wherein each of saidC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected R^(S)substituents;

each M is independently selected from —O—, —C(O)—, —C(O)NR^(L)—,—NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂—, —S(O)₂—, and—S(O)₂NR^(L)—, provided that when M is attached to a nitrogen atom, thenM is selected from —C(O)—, —C(O)NR^(L)—, —S(O)₂—, and —S(O)₂NR^(L)—;

each R^(L) is independently selected from H and C₁₋₃ alkyl; and

each R^(S) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In one embodiment (c):

r is 0, 1, or 2;

u is 0, 1, or 2;

v is 0, 1, or 2;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, then R¹ and R^(1″) are each a bond; and

when n is 0, then R¹ and R^(1″) are each independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R², R³, R⁶, R⁷, R⁸ and each R⁴ are each independently selected from H,halo, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

when s is 1, then R⁵ is a bond;

when s is 0, then R⁵ is selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents;

each R^(2A) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

U is CR^(U);

Y is N;

Z is N;

R^(U) is selected from H, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

Ring moiety A is 5-membered heteroaryl;

Ring moiety B is 5-membered heteroaryl;

Ring C is a 5-membered heteroaryl ring;

each R^(A) and R^(B) is independently selected from H and C₁₋₆ alkyl;

each R^(A) and R^(B) is independently selected from H and C₁₋₆ alkyl;

L¹, L², and L³ are each independently selected from —R—R— and —R—R—R—

R is independently selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene, wherein each of said C₁₋₆ alkylene, C₂₋₆ alkenylene,and C₂₋₆ alkynylene is optionally substituted with 1, 2, 3, or 4substituents independently selected R^(S) substituents; and

each R^(S) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In one embodiment (d):

r is 0, 1, or 2;

u is 0, 1, or 2;

v is 0, 1, or 2;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, then R¹ and R^(1″) are each a bond; and

when n is 0, then R¹ and R^(1″) are each independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R², R³, R⁶, R⁷, R⁸ and each R⁴ are each independently selected from H,halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a2), and C(O)NR^(c2)R^(d2),wherein said C₁₋₆ alkyl and C₁₋₆ haloalkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

when s is 1, then R⁵ is a bond;

when s is 0, then R⁵ is selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR³², and C(O)NR^(c2)R^(d2), wherein said C₁₋₆ alkyl and C₁₋₆haloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents;

each R^(2A) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃alkylamino, di(C₁₋₃ alkyl)amino, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, and di(C₁₋₃ alkyl)carbamyl;

U is CR^(U);

Y is N;

Z is N;

R^(U) is H;

Ring moiety A is a pyrazole ring;

Ring moiety B is a pyrazole ring;

Ring C is furanyl;

each R^(A) and R^(B) is independently selected from H and C₁₋₆ alkyl;

each R^(A) and R^(B) is independently selected from H and C₁₋₆ alkyl;

L¹, L², and L³ are each independently selected from —R—R— and —R—R—R—

R is independently selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene; and

each R^(S) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy,C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio,C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In one embodiment (e):

r is 0, 1, or 2;

u is 0, 1, or 2;

v is 0, 1, or 2;

n is 1;

s is 0;

m is 0;

R², R⁵, R⁶, R⁸, and each R⁴ are each independently selected from H, D,halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy,wherein the C₁₋₆ alkoxy is optionally substituted by HO—C₁₋₃ alkyl orC₁₋₃ alkoxy-C₁₋₃ alkyl;

R³ and R⁷ are each independently selected from OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected from Hand C₁₋₆ alkyl

U is CR^(U);

Y is N;

Z is N;

R^(U) is H;

Ring moiety A is a pyrazole ring;

Ring moiety B is a pyrazole ring;

Ring C is furanyl;

each R^(A) and R^(B) is independently selected from H and C₁₋₆ alkyl;

L¹ is selected from —R—R— and —R—R—R—; and

each R is independently selected from C₁₋₆ alkylene, C₂₋₆ alkenylene,and C₂₋₆ alkynylene.

In one embodiment (f):

r is 0, 1, or 2;

u is 0, 1, or 2;

v is 0, 1, or 2;

n is 1;

s is 0;

m is 0;

R², R⁵, R⁶, R⁸, and each R⁴ are each independently selected from H, D,halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy,wherein the C₁₋₆ alkoxy is optionally substituted by HO—C₁₋₃ alkyl orC₁₋₃ alkoxy-C₁₋₃ alkyl;

R³ and R⁷ are each C(O)NH₂;

U is CR^(U);

Y is N;

Z is N;

R^(U) is H;

Ring moiety A is a pyrazole ring;

Ring moiety B is a pyrazole ring;

Ring C is furanyl;

each R^(A) and R^(B) is independently selected from H and C₁₋₆ alkyl;

L¹ is selected from —R—R— and —R—R—R—; and

each R is independently selected from C₁₋₆ alkylene and C₂₋₆ alkenylene.

In one embodiment (g):

r is 0, 1, or 2;

u is 0, 1, or 2;

v is 0, 1, or 2;

n is 1;

s is 0;

m is 0;

R², R⁶, R⁸, and each R⁴ are each H;

R⁵ is C₁₋₆ alkoxy, which is optionally substituted by HO—C₁₋₃ alkyl orC₁₋₃ alkoxy-C₁₋₃ alkyl;

R³ and R⁷ are each C(O)NH₂;

U is CR^(U);

Y is N;

Z is N;

R^(U) is H;

Ring moiety A is a pyrazole ring;

Ring moiety B is a pyrazole ring;

Ring C is furanyl;

each R^(A) and R^(B) is independently selected from H, methyl, andethyl;

L¹ is selected from —R—R— and —R—R—R—; and

each R is independently selected from C₁₋₆ alkylene and C₂₋₆ alkenylene.

In one embodiment (h):

r is 0, 1, or 2;

u is 0, 1, or 2;

v is 0, 1, or 2;

n is 1;

s is 0;

m is 0;

R², R⁶, R⁸, and each R⁴ are each H;

R⁵ is selected from methoxy, 3-hydroxypropoxy, and 3-methoxypropoxy;

R³ and R⁷ are each C(O)NH₂;

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected from Hand C₁₋₆ alkyl;

U is CR^(U);

Y is N;

Z is N;

R^(U) is H;

Ring moiety A is a pyrazole ring;

Ring moiety B is a pyrazole ring;

Ring C is furanyl;

each R^(A) and R^(B) is independently selected from H, methyl, andethyl; and

L¹ is —CH₂—CH═CH—CH₂—.

In some embodiments, the compound is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (Id):

or a pharmaceutically acceptable salt thereof. In some embodiments ofthe compounds of Formula (Id), R^(U) is H.

In some embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

Formulas (Ia), (Ib), (Ic), (Id), and (II) can be combined with any ofthe aforementioned embodiments. In some embodiments, Formula (Ia) iscombined with embodiment (a); or with embodiment (b); or with embodiment(c); or with embodiment (d); or with embodiment (e); or with embodiment(f); or with embodiment (g); or with embodiment (h). In someembodiments, Formula (Ib) is combined with embodiment (a); or withembodiment (b); or with embodiment (c); or with embodiment (d); or withembodiment (e); or with embodiment (f); or with embodiment (g); or withembodiment (h). In some embodiments, Formula (Ic) is combined withembodiment (a); or with embodiment (b); or with embodiment (c); or withembodiment (d); or with embodiment (e); or with embodiment (f); or withembodiment (g); or with embodiment (h). In some embodiments, Formula(Id) is combined with embodiment (a); or with embodiment (b); or withembodiment (c); or with embodiment (d); or with embodiment (e); or withembodiment (f); or with embodiment (g); or with embodiment (h). In someembodiments, Formula (II) is combined with embodiment (a); or withembodiment (b); or with embodiment (c); or with embodiment (d); or withembodiment (e); or with embodiment (f); or with embodiment (g); or withembodiment (h).

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₄alkyl-”, “alkylene”, “alkenylene” and “alkynylene” linking groups, asdescribed herein, are optionally replaced by deuterium atoms.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (i.e., as if theembodiments are multiply dependent claims). Conversely, various featuresof the invention which are, for brevity, described in the context of asingle embodiment, can also be provided separately or in any suitablesubcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency, that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

When any variable (e.g., R^(S)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 1, 2, 3, or 4 R^(S),then said group may optionally be substituted with up to four R^(S)groups and R^(S) at each occurrence is selected independently from thedefinition of R^(S). Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds;for example the combination of a first M group and second M group in thecombination of two R groups are permissible only if such combinations ofM-M result in stable compounds (e.g., M-M is not permissible if it willform highly reactive compounds such as peroxides having O—O bonds).

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, theterm “C_(n-m) alkoxy”, employed alone or in combination with otherterms, refers to a group of formula-O-alkyl, wherein the alkyl group hasn to m carbons. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g.,n-butoxy and tert-butoxy), and the like. In some embodiments, the alkylgroup has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2 fused rings). The term “C_(n-m)aryl” refers to an aryl group having from n to m ring carbon atoms. Arylgroups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl, and the like. In some embodiments, the aryl group hasfrom 6 to 10 carbon atoms. In some embodiments, the aryl group is phenylor naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In someembodiments, halo is F. In some embodiments, halo is Cl.

As used herein, “C_(n-m)haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m)haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonylamino” refers to a groupof formula —NHC(O)O(C_(n-m) alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m)alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m)alkylthio” refers to a group of formula—S-alkyl, wherein the alkyl group has n to m carbon atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “cyano-C₁₋₆ alkyl” refers to a group of formula—(C₁₋₆ alkylene)-CN. As used herein, the term “cyano-C₁₋₃ alkyl” refersto a group of formula —(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₆ alkyl” refers to a group of formula—(C₁₋₆ alkylene)-OH. As used herein, the term “HO—C₁₋₃ alkyl” refers toa group of formula —(C₁₋₃ alkylene)-OH.

As used herein, the term “C₁₋₆ alkoxy-C₁₋₆ alkyl” refers to a group offormula —(C₁₋₆ alkylene)-O(C₁₋₆ alkyl). As used herein, the term “C₁₋₃alkoxy-C₁₋₃ alkyl” refers to a group of formula —(C₁₋₃ alkylene)-O(C₁₋₃alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms.

In some embodiments, each alkyl group independently has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyloxy” is a group offormula —OC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, “aminocarbonyloxy” is a group of formula —OC(O)—NH₂.

As used herein, “C_(n-m) alkylaminocarbonyloxy” is a group of formula—OC(O)—NH— alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, “di(C_(n-m)alkyl)aminocarbonyloxy” is a group of formula—OC(O)—N(alkyl)₂, wherein each alkyl group has, independently, n to mcarbon atoms. In some embodiments, each alkyl group independently has 1to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein C_(n-m) alkoxycarbonylamino refers to a group of formula—NHC(O)—O— alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 or 14 ring-forming carbons (i.e., C₃₋₁₄). In someembodiments, the cycloalkyl is a C₃₋₁₂ monocyclic or bicyclic cycloalkylwhich is optionally substituted by CH₂F, CHF₂, CF₃, and CF₂CF₃. In someembodiments, the cycloalkyl is a C₃₋₁₀ monocyclic or bicycliccycloalkyl. In some embodiments, the cycloalkyl is a C₃₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₄₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C4-14 spirocycle orbridged cycloalkyl (e.g., a bridged bicycloalkyl group). Examplecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2, 3, or 4 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, and S. In some embodiments, the heteroaryl is a 5-10membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, and S. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, and S. In some embodiments, the heteroaryl is a 5-6monocyclic heteroaryl having 1 or 2 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, theheteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ringmembers independently selected from N, O, and S. In some embodiments,the heteroaryl group contains 3 to 14, 3 to 10, 4 to 14, 4 to 10, 3 to7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroarylgroup has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-formingheteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-formingheteroatom. When the heteroaryl group contains more than one heteroatomring member, the heteroatoms may be the same or different. Exampleheteroaryl groups include, but are not limited to, pyridine, pyrimidine,pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole,thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole,thiadiazole, quinoline, isoquinoline, indole, benzothiophene,benzofuran, benzisoxazole, imidazo[1, 2-b]thiazole, purine, triazine,thieno[3,2-b]pyridine, imidazo[1,2-a]pyridine, 1,5-naphthyridine,1H-pyrazolo[4,3-b]pyridine, and the like.

A five-membered heteroaryl is a heteroaryl group having fivering-forming atoms wherein one or more (e.g., 1, 2, or 3) of thering-forming atoms are independently selected from N, O, S or B.Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1,2-dihydro-1,2-azaborine.

A six-membered heteroaryl ring is a heteroaryl group having sixring-forming atoms wherein one or more (e.g., 1, 2, or 3) of thering-forming atoms are independently selected from N, O, S and B.Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S and B, and wherein the ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(0), S(O), C(S), orS(O)₂, etc.). Heterocycloalkyl groups include monocyclic and polycyclic(e.g., having 2 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 12, 4-12, 3-10-, 4-10-, 3-7-, 4-7-, and5-6-membered heterocycloalkyl groups. Heterocycloalkyl groups can alsoinclude spirocycles and bridged rings (e.g., a 5-14 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 10ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-formingatoms, or 5 to 6 ring-forming atoms. In some embodiments, theheterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkylis a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatomsindependently selected from N, O, S and B and having one or moreoxidized ring members.

Example heterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, 1,2,3,4-tetrahydroisoquinoline,azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl and the like.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, the term “alkylene” refers a divalent straight chain orbranched alkyl linking group. Examples of “alkylene groups” includemethylene, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl,propan-1,2-diyl, propan-1,1-diyl and the like.

As used herein, the term “alkenylene” refers a divalent straight chainor branched alkenyl linking group. Examples of “alkenylene groups”include ethen-1,1-diyl, ethen-1,2-diyl, propen-1,3-diyl,2-buten-1,4-diyl, 3-penten-1,5-diyl, 3-hexen-1,6-diyl, 3-hexen-1,5-diyl,and the like.

As used herein, the term “alkynylene” refers a divalent straight chainor branched alkynyl linking group. Examples of “alkynylene groups”include propyn-1,3-diyl, 2-butyn-1,4-diyl, 3-pentyn-1,5-diyl,3-hexyn-1,6-diyl, 3-hexyn-1,5-diyl, and the like.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent are independently selected ateach occurrence from the applicable list.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula (I), (II), etc.) provided herein include stereoisomers of thecompounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asR-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected.

Partial separation can include, for example, a composition enriched inthe compounds provided herein. Substantial separation can includecompositions containing at least about 50%, at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, at least about 95%,at least about 97%, or at least about 99% by weight of the compoundsprovided herein, or salt thereof. Methods for isolating compounds andtheir salts are routine in the art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. The present disclosure also includespharmaceutically acceptable salts of the compounds described herein. Asused herein, “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts of the present disclosureinclude the conventional non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

As will be appreciated by those skilled in the art, the compoundsprovided herein, including salts and stereoisomers thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

Compounds of formula 1-9 can be synthesized using a process shown inScheme 1. Sonogashira cross-coupling of an appropriately functionalizednitro-halo-phenol (where X′ is the more reactive halogen) compound 1-1with alkyne 1-2 can afford compound 1-3. Ring closure of 1-3 to formcompounds of formula 1-4 may occur in the cross-coupling step;otherwise, compounds of formula 1-4 can be achieved using bases such as,but not limited to, ammonium hydroxide, or potassium carbonate.Nucleophilic aromatic substitution of compound 1-4 with an aminecontaining a linker group [L¹]_(n) 1-5 can afford compound 1-6.Alternatively, transition metal (including, but not limited to, Pd andCu) catalyzed C—N bond forming reactions may also be used to providecompound 1-6. Reduction of the aromatic nitro group followed by ringclosing reaction with cyanogen bromide can provide theaminobenzofuroimidazole 1-7. Amide coupling of compound 1-7 withcarboxylic acid 1-8 can generate the aminobenzofuroimidazole 1-9.

When R⁴=H, compounds of formula 2-7 can be synthesized using a processshown in Scheme 2. Sonogashira cross-coupling of di-halo-benzenecompound 2-1 (in which X′ is the more reactive halogen) with TMSacetylene 2-2 provides alkyne 2-3. Ring closure of 2-3 to form compoundsof formula 1-4 may occur in the cross-coupling step; otherwise,compounds of formula 2-4 can be achieved using bases such as, but notlimited to, ammonium hydroxide, or potassium carbonate. Nucleophilicaromatic substitution of compound 2-4 with amine 2-5 can afford compound2-6. Alternatively, transition metal (e.g. Pd, Cu, etc.) catalyzed C—Nbond forming reactions may also be used to provide compound 2-6.Compounds of formula 2-7 may then be prepared in the same fashion asstated above in Scheme 1.

Compounds of formula 3-7 can be synthesized using a process shown inScheme 3. Benzofuran 3-1 can be brominated to form bromo-benzofuran 3-2,which can then be cross-coupled (via transition metals such as, but notlimited to, Pd, Cu, and Ni) with a suitable metallated reagent 3-3 toform compound 3-4. Nucleophilic aromatic substitution of compound 3-4with amine 3-5 can afford compound 3-6. Alternatively, transition metal(e.g. Pd, Cu, etc.) catalyzed C—N bond forming reactions may also beused to provide compound 3-6. Compounds of formula 3-7 may then beprepared in the same fashion as described above in Scheme 1.

Compounds of formula 4-8 can be synthesized using a process shown inScheme 4. Palladium-catalyzed cross-coupling reactions of theappropriate aryl halides and boronic acids/esters can produce the biarylcompounds of formula 4-5. Suzuki coupling of the aryl-Cl 4-5 witharomatic boronic ester 4-6 can furnish the compounds of formula 4-7.Under deoxygenation conditions, the in-situ generated nitrene fromcompound 4-7 can insert into the adjacent aromatic C—H bond and affordthe tricyclic compound 4-8.

Compounds of formula 5-4 can be synthesized using a process shown inScheme 5. Protected amine 5-1 can first be deprotected, and hydroxylatedusing Sandmeyer protocol. The allylic alcohol can then be converted to abromide using PBr₃ to provide reactant 5-2. Electrophile 5-2 can then bereacted with nucleophile 5-3 using basic conditions to provide compoundsof formula 5-4.

Compounds of formula 6-4 can be synthesized using a process shown inScheme 6. Protected amine 6-1 can first be deprotected, and hydroxylatedusing Sandmeyer protocol. The allylic alcohol can then be converted to abromide using PBr₃ to provide reactant 6-2. Electrophile 6-2 can then bereacted with nucleophile 6-3 using basic conditions to provide compoundsof formula 6-4.

Compounds of formula 7-6 can be synthesized using a process shown inScheme 7. Reagents 7-1 and 7-2 can be coupled with the suitable linkerto form compound 7-3. Saponification of compound 7-3 can afford compound7-4. Amide coupling of molecule 7-4 with 2-amino-benzimidazole 7-5 cangenerate the target molecule 7-6.

Compounds of formula 8-7 can be synthesized using a process shown inScheme 8. Reagents 8-1 and 8-2 can be coupled with the suitable linkerto form compound 8-3. Reduction of the aromatic nitro group followed byring closing reaction with cyanogen bromide can provide theaminobenzimidazole 8-5. Amide coupling of compound 8-5 with carboxylicacid 8-6 can generate the target molecule 8-7.

Compounds of formula 9-10 can be synthesized using a process shown inScheme 9.

Protected amine (where P can include, but is not limited to, Boc, Fmoc,phthalimide, etc.) 9-1 and ester (where P′=alkyl, which includes, but isnot limited to methyl, ethyl, tert-butyl, etc.) 9-2 can be coupled withthe suitable linker to form compound 9-3. Removal of the protectinggroup, P, in 9-3 and sequential nucleophilic aromatic substitution withhalo-nitro-phenyl 9-5 can afford compound 9-6. Alternatively, transitionmetal (e.g. Pd, Cu, etc.) catalyzed C—N bond forming reactions may alsobe used to provide compound 9-6. Reduction of the aromatic nitro group,followed by ring closing reaction with cyanogen bromide andintramolecular amide coupling with either the ester 9-8 or acidderivative 9-9 (generated through suitable deprotection conditions of9-8) can provide the target compound 9-10.

Compounds of formula 10-8 can be synthesized using a process shown inScheme 10. Reagent 10-1 and protected amine (where P can include, but isnot limited to, Boc, Fmoc, phthalimide, etc.) 10-2 can be coupled withthe suitable linker to form compound 10-3. Removal of the protectinggroup, P, in 10-3 and sequential intramolecular nucleophilic aromaticsubstitution can afford compound 10-5. Reduction of the aromatic nitrogroup followed by ring closing reaction with cyanogen bromide and amidecoupling with carboxylic acid 10-7 can generate the target molecule10-8.

Compounds of formula 11-7 can be synthesized using a process shown inScheme 11. Reagent 11-1 and ester (where P′=alkyl, which includes, butis not limited to methyl, ethyl, tert-butyl, etc.) 11-2 can be coupledwith the suitable linker to form compound 11-3. Next, reagent 11-3 couldbe further coupled with compound 11-4 by linker [L³]s to accessintermediate 11-5. Finally, target compounds 11-7 can be accessed froman intramolecular amide coupling with either the ester 11-5 or acidderivative 11-6 (generated through suitable deprotection conditions ofderivative 11-5).

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

The expressions, “ambient temperature” or “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g., a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

Methods of Use

Compounds of the present disclosure can activate STING-mediated IRF3 andNFκB signaling pathways to produce type I interferons andproinflammatory chemokines and cytokines and, thus, are useful intreating infectious diseases and cancer. In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in cancer,chronic infection or sepsis, including enhancement of response tovaccination. In some embodiments, the present disclosure provides amethod for inducing STING-mediated IRF3 and NFκB pathway activation. Themethod includes administering to an individual or a patient a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or apharmaceutically acceptable salt or a stereoisomer thereof. Thecompounds of the present disclosure can be used alone, in combinationwith other agents or therapies or as an adjuvant or neoadjuvant for thetreatment of diseases or disorders, including cancer or infectiondiseases. For the uses described herein, any of the compounds of thedisclosure, including any of the embodiments thereof, may be used.

The compounds of the present disclosure activate STING, resulting inIRF3 and NFκB upregulation and production of IFNs and other cytokines.The production of those interferons and proinflammatory cytokines canenhance the immune response to cancerous cells and infectious diseasesin mammals, including humans. In some embodiments, the presentdisclosure provides treatment of an individual or a patient in vivousing a compound of Formula (I) or a salt or stereoisomer thereof suchthat growth of cancerous tumors is inhibited. A compound of Formula (I)or of any of the formulas as described herein, or a compound as recitedin any of the claims and described herein, or a salt or stereoisomerthereof, can be used to inhibit the growth of cancerous tumors.Alternatively, a compound of Formula (I) or of any of the formulas asdescribed herein, or a compound as recited in any of the claims anddescribed herein, or a salt or stereoisomer thereof, can be used inconjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells in an individualor a patient.

The method includes administering to the individual or patient in needthereof a therapeutically effective amount of a compound of Formula (I)or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or a salt or astereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

In some embodiments, the present disclosure provides a method ofenhancing, stimulating and/or increasing the immune response in apatient. The method includes administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound or composition asrecited in any of the claims and described herein, or a salt thereof.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, Merkel cell carcinoma, brain stem glioma, pituitaryadenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer,T-cell lymphoma, environmentally induced cancers including those inducedby asbestos, and combinations of said cancers. The compounds of thepresent disclosure are also useful for the treatment of metastaticcancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer, lungcancer (e.g. non-small cell lung cancer and small cell lung cancer),squamous cell head and neck cancer, urothelial cancer (e.g. bladder) andcancers with high microsatellite instability (MSI^(high)). Additionally,the disclosure includes refractory or recurrent malignancies whosegrowth may be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, and keloids. In some embodiments, diseases andindications that are treatable using the compounds of the presentdisclosure include, but are not limited to, sickle cell disease (e.g.,sickle cell anemia), triple-negative breast cancer (TNBC),myelodysplastic syndromes, testicular cancer, bile duct cancer,esophageal cancer, and urothelial carcinoma.

Induction of type I interferons and other proinflammatorycytokines/chemokines with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria, fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,a salt thereof. Examples of viruses causing infections treatable bymethods of the present disclosure include, but are not limit to, humanimmunodeficiency virus, human papillomavirus, influenza, hepatitis A, B,C or D viruses, adenovirus, poxvirus, herpes simplex viruses, humancytomegalovirus, severe acute respiratory syndrome virus, ebola virus,and measles virus. In some embodiments, viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus,flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus,respiratory syncytial virus, mumpsvirus, rotavirus, measles virus,rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus,papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus,tuberculosis and arboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic bacteria causing infections treatable by methodsof the disclosure include Chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, diphtheria,salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Non-limiting examples ofpathogenic fungi causing infections treatable by methods of thedisclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic parasites causing infections treatable by methodsof the disclosure include Entamoeba histolytica, Balantidium coli,Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidiumsp., Pneumocystis carinii, Plasmodium vivax, Babesia microti,Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasmagondi, and Nippostrongylus brasiliensis.

The present disclosure provides a method for treating neurodegenerativediseases or disorders. The method includes administering to a patient inneed thereof, a therapeutically effective amount of a compound ofFormula (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof.Non-limiting examples of neurodegenerative diseases or disorders includeAlzheimer's disease, Parkinson's disease, Huntington's disease, priondisease, Motor neurone diseases, Spinocerebellar ataxia and Spinalmuscular atrophy.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies I. Immune-Checkpoint Therapies

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3Kgamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR,B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1,PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule isa stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. Insome embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1monoclonal antibody is nivolumab or pembrolizumab. In some embodiments,the anti-PD1 antibody is pembrolizumab. In some embodiments, theanti-PD-1 monoclonal antibody is MGA012. In some embodiments, theanti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) includeantibody therapeutics such as 4-1BB (e.g. urelumab, utomilumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In someembodiments, the inhibitor of an immune checkpoint molecule is aninhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 bispecificantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, and FAK kinase inhibitors such as, forexample, those described in WO 2006/056399. Other agents such astherapeutic antibodies can be used in combination with the compounds ofthe present disclosure for treatment of STING-associated diseases,disorders, or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

The compounds as disclosed herein can be used in combination with one ormore other enzyme/protein/receptor inhibitors therapies for thetreatment of diseases, such as cancer and other diseases or disordersdescribed herein. Examples of diseases and indications treatable withcombination therapies include those as described herein. Examples ofcancers include solid tumors and non-solid tumors, such as liquidtumors, blood cancers. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections. Forexample, the compounds of the present disclosure can be combined withone or more inhibitors of the following kinases for the treatment ofcancer: Akt1, Akt2, Akt3, BCL2, CDK, TGF-PR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma,delta, and multiple or selective), CSF1R, KIT, FLK-II, KDR/FLK-1, FLK-4,flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB,TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2, Flt4, EphA1,EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK,FRK, JAK, ABL, ALK and B-Raf. In some embodiments, the compounds of thepresent disclosure can be combined with one or more of the followinginhibitors for the treatment of cancer or infections. Non-limitingexamples of inhibitors that can be combined with the compounds of thepresent disclosure for treatment of cancer and infections include anFGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., pemigatinib(INCY54828), INCB62079), an EGFR inhibitor (also known as ErB-1 orHER-1; e.g. erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab,necitumumab, or panitumumab), a VEGFR inhibitor or pathway blocker (e.g.bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib,ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib,ziv-aflibercept), a PARP inhibitor (e.g. olaparib, rucaparib, veliparibor niraparib), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib, itacitinib (INCB39110), an IDO inhibitor (e.g.,epacadostat, NLG919, or BMS-986205, MK7162), an LSD1 inhibitor (e.g.,INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g.,INCB50465 and INCB50797), a PI3K-gamma inhibitor such as PI3K-gammaselective inhibitor, a Pim inhibitor (e.g., INCB53914), a CSF1Rinhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), anadenosine receptor antagonist (e.g., A2a/A2b receptor antagonist), anHPK1 inhibitor, a chemokine receptor inhibitor (e.g. CCR2 or CCR5inhibitor), a SHP1/2 phosphatase inhibitor, a histone deacetylaseinhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor,an interleukin receptor inhibitor, bromo and extra terminal familymembers inhibitors (for example, bromodomain inhibitors or BETinhibitors such as INCB54329 and INCB57643), or combinations thereof.

In some embodiments, the compound or salt described herein isadministered with a PI3K6 inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C,adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine,ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, bispecific ormulti-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3K6 inhibitor and the like. The compounds can beadministered in combination with one or more anti-cancer drugs, such asa chemotherapeutic agent. Examples of chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotiib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present disclosure with anadditional agent.

In some embodiments, the compounds of the disclosure can be used incombination with an inhibitor of JAK or PI3K6.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of thedisclosure where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, Chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, Klebsiella, Proteus, Serratia, Pseudomonas,Legionella, diphtheria, Salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating STING in tissue samples,including human, and for identifying STING activators by inhibitionbinding of a labeled compound. Substitution of one or more of the atomsof the compounds of the present disclosure can also be useful ingenerating differentiated ADME (Adsorption, Distribution, Metabolism andExcretion.) Accordingly, the present disclosure includes STING assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsof the disclosed Formulas (e.g., Formula (I)) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuteriumatoms. In some embodiments, all of the hydrogen atoms in a compound canbe replaced or substituted by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents or —C₁₋₄ alkyl-, alkylene,alkenylene and alkynylene linking groups, as described herein, areoptionally replaced by deuterium atoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro STING labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S canbe useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind activate STING by monitoring itsconcentration variation when contacting with STING, through tracking ofthe labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to STING (i.e., standard compound).

Accordingly, the ability of a test compound to compete with the standardcompound for binding to STING directly correlates to its bindingaffinity. Conversely, in some other screening assays, the standardcompound is labeled and test compounds are unlabeled.

Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of STING-associated diseases ordisorders (such as, e.g., cancer, an inflammatory disease, acardiovascular disease, or a neurodegenerative disease) which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfirerm C₁₈ 5 μm, 30×100 mm or WatersXBridge™ C₁₈ 5 μm, 30×100 mm column, eluting with mobile phase A: 0.1%TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile;the flow rate was 60 mL/minute, the separating gradient was optimizedfor each compound using the Compound Specific Method Optimizationprotocol as described in the literature (see e.g. “Preparative LCMSPurification: Improved Compound Specific Method Optimization”, K. Blom,B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

pH=10 purifications: Waters XBridge™ C₁₈ 5 μm, 30×100 mm column, elutingwith mobile phase A: 0.1% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 60 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)).

Example 1.(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

Step 1: methyl 2-bromo-4-chloro-3-hydroxy-5-nitrobenzoate

To a solution of t-butylamine (1.774 mL, 16.88 mmol) in dry toluene(11.25 mL) was added bromine (0.319 mL, 6.19 mmol) dropwise at −30° C.(˜10 min) under nitrogen. The mixture was cooled to −78° C., and asolution of methyl 4-chloro-3-hydroxy-5-nitrobenzoate (Combi-Blocks, cat#CA-5786: 1.3030 g, 5.63 mmol) in DCM (45.0 mL) was added dropwise undernitrogen (˜30 min). The mixture was warmed to room temperature (rt)gradually and stirred overnight. The reaction was diluted with EtOAc andthe organic phase washed with 1.0 M HCl (2×) and brine (1×). The organicphase was dried over anhydrous MgSO₄, filtered, and the filtrateevaporated under reduced pressure. The residue was purified by flashchromatography (10% EtOAc/hexanes) to give the desired product as awhite solid. LC-MS calculated for C₈H₆BrClNO₅ (M+H)⁺: m/z=309.9/311.9;found 309.8/312.0.

Step 2: methyl 3-acetoxy-2-bromo-4-chloro-5-nitrobenzoate

To a solution of methyl 2-bromo-4-chloro-3-hydroxy-5-nitrobenzoate (1.37g, 4.41 mmol) and triethylamine (1.845 mL, 13.24 mmol) in CH₂Cl₂ (12.98mL) was added Ac₂O (0.541 mL, 5.74 mmol) at 0° C. After stirring for 18h at rt, the mixture was diluted with HCl (1 M, 10 mL). The resultingmixture was extracted with CH₂Cl₂ (3×10 mL). The combined organic layerswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude residue was then purified by flash chromatography (10%EtOAc/hexanes) to provide the desired product as a white solid. LC-MScalculated for C₁₀H₈BrClNO₆ (M+H)⁺: m/z=351.9/353.9; found 351.9/353.8.¹H NMR (500 MHz, DMSO) δ 8.48 (s, 1H), 3.92 (s, 3H), 2.49 (s, 3H). ¹³CNMR (125 MHz, DMSO) δ 167.0, 163.6, 147.0, 146.8, 132.8, 124.4, 124.1,122.1, 53.4, 20.0.

Step 3: methyl3-acetoxy-4-chloro-5-nitro-2-((trimethylsilyl)ethynyl)benzoate

Methyl 3-acetoxy-2-bromo-4-chloro-5-nitrobenzoate (0.503 g, 1.427 mmol),cuprous iodide (0.027 g, 0.143 mmol) anddichlorobis(triphenylphosphine)-palladium(II) (0.050 g, 0.071 mmol) wereadded in a vial and the vial was sealed, evacuated and flushed withnitrogen (3×). Then DMF (3.57 mL) and DIPEA (1.189 mL) were added undernitrogen. Next, ethynyltrimethylsilane (0.605 mL, 4.28 mmol) was addedand reaction mixture was stirred at 35° C. overnight. After cooling tort, the mixture was diluted with DCM and 1 N HCl. The layers wereseparated, and the aqueous layer was further extracted. The combinedorganic layers were dried over MgSO4, filtered, and concentrated invacuo. The crude residue was then purified by flash chromatography (10%EtOAc/hexanes) to provide the desired product as a clear solid. LC-MScalculated for C₁₅H₁₇ClNO₆Si (M+H)⁺: m/z=370.0; found 370.0.

Step 4: methyl 4-chloro-2-ethynyl-3-hydroxy-5-nitrobenzoate

To a solution of methyl3-acetoxy-4-chloro-5-nitro-2-((trimethylsilyl)ethynyl)benzoate (0.331 g,0.895 mmol) in MeOH (8.95 mL) was added potassium carbonate (0.124 g,0.895 mmol). The reaction mixture was stirred for 15 min, and was thendiluted with DCM and 1 N HCl. The layers were separated, and the aqueouslayer was further extracted with DCM. The combined organic layers weredried over MgSO₄, filtered, and concentrated in vacuo. The resultingresidue was then used directly in the next step without furtherpurification. LC-MS calculated for C₁₀H₇ClNO₅ (M+H)⁺: m/z=256.0; found256.1.

Step 5: 7-chloro-6-nitrobenzofuran-4-carboxamide

To a vial was added methyl 4-chloro-2-ethynyl-3-hydroxy-5-nitrobenzoate(201 mg, 0.786 mmol) and ammonium hydroxide (9186 μl, 236 mmol). Themixture was stirred at rt for 20 h, and was then filtered. The resultingsolid was washed with water, dried, and used directly in the next stepwithout further purification. LC-MS calculated for C₉H₆ClN₂O₄ (M+H)⁺:m/z=241.0; found 241.0. ¹H NMR (500 MHz, DMSO) δ 8.53 (s, 1H), 8.51 (d,J=2.25 Hz, 1H), 8.35 (s, 1H), 7.76 (s, 1H), 7.54 (d, J=2.25 Hz, 1H). ¹³CNMR (125 MHz, DMSO) δ 165.6, 152.7, 150.6, 142.6, 131.5, 126.0, 120.0,113.5, 108.8.

Step 6: tert-butyl(E)-(4-((4-carbamoyl-6-nitrobenzofuran-7-yl)amino)but-2-en-1-yl)carbamate

To a vial was added tert-butyl (E)-(4-aminobut-2-en-1-yl)carbamate(Enamine, cat #EN300-134337: 0.07 g, 0.376 mmol),7-chloro-6-nitrobenzofuran-4-carboxamide (0.090 g, 0.376 mmol), a stirbar, DMSO (1.879 mL), and DIPEA (0.328 mL, 1.879 mmol). The resultingmixture was sealed and heated at 100° C. for 8 h. After cooling to rt,the mixture was concentrated and purified by column chromatography (10%MeOH/DCM). LC-MS calculated for C₁₈H₂₂N₄O₆Na (M+Na)+: m/z=413.2; found413.2.

Step 7: (tert-butyl(E)-(4-((6-amino-4-carbamoylbenzofuran-7-yl)amino)but-2-en-1-yl)carbamate

To a solution of tert-butyl(E)-(4-((4-carbamoyl-6-nitrobenzofuran-7-yl)amino)but-2-en-1-yl)carbamate(0.150 g, 0.384 mmol) in dioxane (2.88 mL))/water (0.961 mL) was addedammonium chloride (0.082 g, 1.537 mmol) and zinc (0.100 g, 1.537 mmol)at 0° C. The reaction mixture was stirred at rt for 10 min, after whichtime it was filtered. The filtrate was partitioned between water (10 mL)and EtOAc (30 mL). The organic layer was separated, dried over MgSO4,concentrated, and dried under high vacuum to provide the product as anorange foam. The orange solid was washed with MeCN to provide thedesired product as a yellow solid. LC-MS calculated for C₁₈H₂₄N₄O₄Na(M+Na)⁺: m/z=383.2; found 383.2.

Step 8: tert-butyl(E)-(4-(2-amino-5-carbamoyl-1H-benzofuro[6,7-d]imidazol-1-yl)but-2-en-1-yl)carbamate

To a solution of tert-butyl(E)-(4-((6-amino-4-carbamoylbenzofuran-7-yl)amino)but-2-en-1-yl)carbamate(0.107 g, 0.297 mmol) in MeOH (1.484 mL) was added cyanogen bromide(0.023 mL, 0.445 mmol). The mixture was stirred at rt for 20 min. Thereaction was concentrated and triturated with EtOAc and filtered toprovide the desired compound as an orange solid. LC-MS calculated forC₁₉H₂₄N₅O₄ (M+H)⁺: m/z=386.2; found 386.2.

Step 9: tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazol-1-yl)but-2-en-1-yl)carbamate

To a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid(Combi-Blocks, cat #QB-0979: 0.050 g, 0.325 mmol) in DMF (1.109 mL) atrt was added HATU (0.146 g, 0.385 mmol) and DIPEA (0.258 mL, 1.479mmol). The mixture was stirred for 15 min, then a solution of tert-butyl(E)-(4-(2-amino-5-carbamoyl-1H-benzofuro[6,7-d]imidazol-1-yl)but-2-en-1-yl)carbamate(0.114 g, 0.296 mmol) in DMF (0.370 mL) was added and stirred overnight.The reaction was concentrated, and was diluted with water. The aqueousmixture was extracted with DCM (3×20 mL). The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The product was purified by column chromatography (15% MeOH/DCM) toprovide the desired product as a white solid. LC-MS calculated forC₂₆H₃₂N₇O₅ (M+H)⁺: m/z=522.2; found 522.3.

Step 10:(E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

To a solution of tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazol-1-yl)but-2-en-1-yl)carbamate(0.124 g, 0.238 mmol) in 1,4-dioxane (2.377 mL) was added 1 N HCl in1,4-dioxane (2.377 mL, 2.377 mmol). The resulting solution was stirredfor 1 h, then concentrated to provide the desired product as its HClsalt. LCMS calculated for C₂₁H₂₄N₇O₃ (M+H)⁺: m/z=422.2; found 422.3.

Step 11:(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

To a solution of(E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide(0.058 g, 0.138 mmol) in THF (0.917 mL) and water (0.917 mL) was addedpotassium bromide (0.025 g, 0.206 mmol) and sodium nitrite (0.014 g,0.206 mmol). The mixture was stirred 1 h at rt, and was diluted with 3:1CHCl₃/IPA and water. The layers were separated and the aqueous layer wasfurther extracted. The combined organic layers were dried over MgSO₄,filtered, and concentrated in vacuo. The crude product was used directlyin the next step without further purification. LC-MS calculated forC₂₁H₂₃N₆O₄ (M+H)⁺: m/z=423.2; found 423.1.

Step 12:(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

To a solution of(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzofuro[6,7-d]imidazole-5-carboxamide(0.058 g, 0.137 mmol) in THF (0.917 mL) was added PBr₃ (0.019 mL, 0.206mmol). The reaction was stirred for 30 min at rt, then quenched withsaturated aqueous sodium bicarbonate. The mixture was diluted with DCMand the layers were separated. The aqueous layer was further extracted,and the combined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude product was used directly in the nextstep without further purification. LC-MS calculated forC₂₁H₂₂BrN₆O₃(M+H)⁺: m/z=485.1, 487.1; found 485.1, 487.1.

Step 13: 3-bromo-5-fluoro-4-nitrobenzamide

Methyl 3-bromo-5-fluoro-4-nitrobenzoate (AstaTech, cat #AB9640: 5.0 g,17.98 mmol) was stirred in ammonium hydroxide (44.1 mL, 1133 mmol) atroom temperature for 10 h. The solid was filtered and rinsed with coldwater. The resulting solid residue was dried to provide the desiredproduct as a light yellow solid.

Step 14: 3-bromo-5-methoxy-4-nitrobenzamide

To a stirred solution of 3-bromo-5-fluoro-4-nitrobenzamide (1.0 g, 3.80mmol) in MeOH (19.01 mL) was added sodium methoxide (1.232 g, 5.70mmol). The reaction mixture was stirred at 60° C. for 0.5 h. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in water, and then extracted with DCM. The combinedorganic layers were dried, filtered, and concentrated in vacuo. Thecrude product was used directly without further purification. LC-MScalculated for C₈H₈BrN₂O₄(M+H)⁺: m/z=275.0, 277.0; found 275.0, 277.0.

Step 15:3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide

To a degassed solution of (2-chloropyrimidin-5-yl)boronic acid(Combi-Blocks, cat #BB-5457: 82 mg, 0.52 mmol) and3-bromo-5-methoxy-4-nitrobenzamide (143 mg, 0.520 mmol) in dioxane (1733μl) and water (347 μl) was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (25.5 mg, 0.031 mmol) and sodium carbonate (110mg, 1.040 mmol). The reaction was stirred at 100° C. for 2 h. Then,1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Enamine Ltd, cat #EN300-207291: 123.0 mg, 0.520 mmol) was added. Thereaction mixture was heated to 100° C. for another 1 h. H₂O was added tothe reaction mixture, and the reaction was extracted with DCM. Thecombined organic layers were dried with Na₂SO₄, filtered, andconcentrated. The crude residue was purified by flash chromatography ona silica gel column eluting with 0 to 8% MeOH in DCM to afford thedesired product. LC-MS calculated for C₁₈H₁₉N₆O₄ (M+H)⁺: m/z=383.1;found 383.2.

Step 16:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide(280.0 mg, 0.732 mmol) and 1,2-bis(diphenylphosphino)ethane (365 mg,0.915 mmol) was dissolved in 1,2-dichlorobenzene (2.4 mL). The vial wasflushed with nitrogen before heating at 160° C. for 1 h. After removalof the solvent under vacuum, the reaction mixture was extracted with DCMand water. The organic phases were combined and dried over MgSO₄,filtered, then concentrated under reduced pressure. The crude residuewas purified by flash chromatography on a silica gel column eluting with0 to 8% MeOH in DCM to afford the desired product. LC-MS calculated forC₁₈H₁₉N₆O₂ (M+H)⁺: m/z=351.1; found 351.1.

Step 17:(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

To a solution of(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide(5 mg, 10.30 μmol) (12634-34-cl) and2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide(3.97 mg, 0.011 mmol) (12634-63-hplc-pk1) in DMF (103 μL) was addedDIPEA (5.40 μL, 0.031 mmol). After 20 min, Cs₂CO₃ (10.07 mg, 0.031 mmol)was added.

The mixture was stirred at rt overnight. The mixture was diluted withMeCN and water, acidified with TFA, then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₉H₃₉N₁₂O₅ (M+H)⁺: m/z=755.3; found 755.3.

Example 2.(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

Step 1: 3-bromo-5-(3-methoxypropoxy)-4-nitrobenzamide

To dry THF (12.67 mL) was added 60% sodium hydride (0.304 g, 7.60 mmol).While stirring, 3-methoxypropan-1-ol (Aldrich, cat #38457: 0.364 mL,3.80 mmol) was added slowly and the mixture was stirred at roomtemperature for 10 min. To the solution of sodium alkoxide was added3-bromo-5-fluoro-4-nitrobenzamide (1.00 g, 3.80 mmol). The reactionmixture was heated to 60° C. for 0.5 h. The resulting mixture wascarefully diluted with water, and extracted with DCM. The combinedorganic layers were dried over MgSO₄, filtered, concentrated in vacuo,and used directly in the next step without further purification. LC-MScalculated for C₁₁H₁₄BrN₂O₅(M+H)⁺: m/z=333.0, 335.0; found 333.0, 335.0.

Step 2:3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-(3-methoxypropoxy)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 1, Step 15 with 3-bromo-5-(3-methoxypropoxy)-4-nitrobenzamidereplacing 3-bromo-5-methoxy-4-nitrobenzamide. LC-MS calculated forC₂₁H₂₅N₆O₅ (M+H)⁺: m/z=441.2; found 441.3.

Step 3:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 16 with3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-(3-methoxypropoxy)-4-nitrobenzamidereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.LC-MS calculated for C₂₁H₂₅N₆O₃ (M+H)⁺: m/z=409.2; found 409.2.

Step 4:(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 17 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamidereplacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₄₂H₄₅N₁₂O₆(M+H)⁺: m/z=813.4; found 813.3. ¹H NMR(600 MHz, DMSO) δ 12.97 (s, 1H), 9.48 (s, 1H), 8.41 (s, 1H), 8.04 (s,1H), 7.85 (d, J=2.0 Hz, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H),7.31 (s, 1H), 6.77 (s, 1H), 6.44 (s, 1H), 5.97 (d, J=15.6 Hz, 1H), 5.79(d, J=15.6 Hz, 1H), 5.35-5.17 (m, 2H), 5.07-4.80 (m, 2H), 4.58 (q, J=7.2Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 4.12-3.98 (m, 2H), 3.26 (m, 2H), 3.13(s, 3H), 2.19 (s, 3H), 2.08 (s, 3H), 1.76 (m, 2H), 1.27-1.07 (m, 6H).

Example 3.(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

Step 1:3-bromo-5-(3-(tert-butyldimethylsilyloxy)propoxy)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 2, Step 1 with 3-((tert-butyldimethylsilyl)oxy)propan-1-ol(Combi-Blocks, cat #QH-3826) replacing 3-morpholinopropan-1-ol. LC-MScalculated for C₁₆H₂₆BrN₂O₅Si (M+H)⁺: m/z=433.1, 435.1; found 433.2,435.2.

Step 2:3-(3-(tert-butyldimethylsilyloxy)propoxy)-5-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 1 Step 15 with3-bromo-5-(3-(tert-butyldimethylsilyloxy)propoxy)-4-nitrobenzamidereplacing 3-bromo-5-methoxy-4-nitrobenzamide. LC-MS calculated forC₂₆H₃₇N₆O₅Si (M+H)⁺: m/z=541.3; found 541.3.

Step 3:8-(3-(tert-butyldimethylsilyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 16 with3-(3-(tert-butyldimethylsilyloxy)propoxy)-5-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-4-nitrobenzamidereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.LC-MS calculated for C₂₆H₃₇N₆O₃Si (M+H)⁺: m/z=509.3; found 509.3.

Step 4:(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 17 with8-(3-(tert-butyldimethylsilyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamidereplacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.The primary alcohol was deprotected during the process. Otherwise, theTBS group could be removed with the addition of 4 equivalents of HCl(0.015 mL of 4 M HCl in dioxane), followed by stirring at roomtemperature for 1 h. The reaction mixture was diluted with MeOH andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as its TFA salt. LC-MS calculated for C₄₁H₄₃N₁₂O₆(M+H)⁺:m/z=799.3; found 799.4.

Example A. IRF3 and NF-kB Activation Assays

THP-1 Dual Cells (Invivogen) were maintained in RPMI1640 medium withaddition of 10% FBS, 100 μg/mL zeocin, 10 μg/mL blasticidin. Cells wereadded in a 96-well flat bottom assay plate at 100,000 per well in 100 μLcomplete RPMI medium. Test compounds were prepared by serial dilution incomplete RPMI medium and 100 μL test compounds were transferred to eachcorresponding well. The assay plate was incubated at 37° C., 5% CO₂ for24 hours. After the overnight incubation, 20 μL of the culturesupernatants were collected, followed by addition of 180 μL ofQUANTI-Blue (Invivogen) to assess IRF3 activity. The amount of IRF3activation was assessed by reading the absorbance at 620-655 nm with amicroplate reader 2 hours later. The culture supernatant from theuntreated THP-1 cells was used as the negative control. To determine theNF-κB activation, another 20 μL of culture supernatant were transferredto a 96-well white plate, followed by addition of 50 μL of Quanti-Luc™assay solution (Invivogen). The amount of NF-κB activation induced bythe test compounds were determined by the luminescence above theuntreated control. EC₅₀ determination was performed by fitting the curveof percent control activity versus the log of the compound concentrationusing the GraphPad Prism 6.0 software.

EC₅₀ in activating IRF3 for the compounds of the Examples are presentedin Table 1.

TABLE 1 Example THP1 IRF3 EC₅₀ No. (nM) 1 + 2 + 3 + + means <100 nM

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: r is 0, 1, 2, 3,or 4; u is 0, 1, 2, 3, or 4; v is 0, 1, 2, 3, or 4; R², R³, R⁵, R⁶, R⁷,R⁸ and each R⁴ are each independently selected from H, D, halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a2), SR^(a2), NHOR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)NR^(c2)(OR^(a2)), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))R^(b2), NR^(c2)S(O)NR^(c2)R^(d2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)(═NR^(e2))R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),S(O)₂NR^(c2)R^(d2), OS(O)(═NR^(e2))R^(b2), OS(O)₂R^(b2), SF₅,P(O)R^(f2)R^(g2), OP(O)(OR^(h2))(OR^(i2)), P(O)(OR^(h2))(OR^(i2)), andBR^(j2)R^(k2), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents; each R^(a2), R^(c2), andR^(d2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; or, any R^(c2) and R^(d2) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; each R^(b2) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents; each R^(e2) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl; each R^(f2) and R^(g2) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;each R^(h2) and R^(i2) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;each R^(j2) and R^(k2) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j2) and R^(k2) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(2A) is independently selected from H, D, halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a21), SR^(a21), NHOR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21),C(O)NR^(c21)(OR^(a21)), C(O)OR^(a21), OC(O)R^(b21),OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21), NR^(c21)NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),C(═NR^(e21))R^(b21), C(═NR^(e21))NR^(c21)R^(d21),NR^(c21)C(═NR^(e21))NR^(c21)R^(d21), NR^(c21)C(═NR^(e21))R^(b21),NR^(c21)S(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21), NR^(c21)S(O)₂R^(b21),NR^(c21)S(O)(═NR^(e21))R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21),S(O)R^(b21), S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21),OS(O)(═NR^(e21))R^(b21), OS(O)₂R^(b21), SF₅, P(O)R^(f21)R^(g21),0P(O)(OR^(h21))(OR^(i21)), P(O)(OR^(h21))(OR^(i21)), andBR^(j21)R^(k21), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents; each R^(a21), R^(c21), andR^(d21) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(2B) substituents; or, any R^(c21)and R^(d21) attached to the same N atom, together with the N atom towhich they are attached, form a 5- or 6-membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5- or 6-membered heteroarylor 4-7 membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(2B) substituents; each R^(b21) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, which are each optionally substituted with 1, 2,3, or 4 independently selected R^(2B) substituents; each R^(e21) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(f21) and R^(g21) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl; each R^(h21) and R^(i21) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(j21) and R^(k21) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j21) and R^(k21) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(2B) is independently selected from H, D, halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a22), SR^(a22), NHOR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22),C(O)NR^(c22)(OR^(a22)), C(O)OR^(a22), OC(O)R^(b22),OC(O)NR^(c22)R^(d22), NR^(c22)R^(d22), NR^(c22)NR^(c22)R^(d22),NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22), NR^(c22)C(O)NR^(c22)R^(d22),C(═NR^(e22))R^(b22), C(═NR^(e22))NR^(c22)R^(d22),NR^(c22)C(═NR^(e22))NR^(c22)R^(d22), NR^(c22)C(═NR^(e22))R^(b22),NR^(c22)S(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22), NR^(c22)S(O)₂R^(b22),NR^(c22)S(O)(═NR^(e22))R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22),S(O)R^(b22), S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22),OS(O)(═NR^(e22))R^(b22), OS(O)₂R^(b22), SF₅, P(O)R^(f22)R^(g22),0P(O)(OR^(h22))(OR^(i22)), P(O)(OR^(h22))(OR^(i22)), andBR^(j22)R^(k22), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents; each R^(a22), R^(c22), andR^(d22) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(S) substituents; or, any R^(c22)and R^(d22) attached to the same N atom, together with the N atom towhich they are attached, form a 5- or 6-membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5- or 6-membered heteroarylor 4-7 membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(S) substituents; each R^(b22) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, which are each optionally substituted with 1, 2,3, or 4 independently selected R^(S) substituents; each R^(e22) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(f22) and R^(g22) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl; each R^(h22) and R^(i22) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(j22) and R^(k22) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j22) and R^(k22) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; U is N or CR^(U); Y is N or CR^(Y); Z is N or CR^(Z); wherein(i) Z is CR^(Z), U is CR^(U), and Y is CR^(Y); or (ii) Z is N, U isCR^(U), and Y is CR^(Y); or (iii) Z is CR^(Z), U is N, and Y is CR^(Y);or (iv) Z is CR^(Z), U is CR^(U), and Y is N; or (v) Z is N, U is N, andY is CR^(Y); or (vi) Z is CR^(Z), U is N, and Y is N; or (vii) Z is N, Uis CR^(U), and Y is N; R^(U), R^(Y), and R^(Z) are each independentlyselected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10membered heteroaryl-C₁₋₄ alkyl, OR^(a0), SR^(a0), NHOR^(a0), C(O)R^(b0),C(O)NR^(c0)R^(d0), C(O)NR^(c0)(OR^(a0)), C(O)OR^(a0), OC(O)R^(b0),OC(O)NR^(c0)R^(d0), NR^(c0)R^(d0), NR^(c0)NR^(c0)R^(d0),NR^(c0)C(O)R^(b0), NR^(c0)C(O)OR^(a0), NR^(c0)C(O)NR^(c0)R^(d0),C(═NR^(e0))R^(b0), C(═NR^(e0))NR^(c0)R^(d0),NR^(c0)C(═NR^(e0))NR^(c0)R^(d0), NR^(c0)C(═NR^(e0))R^(b0),NR^(c0)S(O)NR^(c0)R^(d0), NR^(c0)S(O)R^(b0), NR^(c0)S(O)₂R^(b0),NR^(c0)S(O)(═NR^(e0))R^(b0), NR^(c0)S(O)₂NR^(c0)R^(d0), S(O)R^(b0),S(O)NR^(c0)R^(d0), S(O)₂R^(b0), S(O)₂NR^(c0)R^(d0),OS(O)(═NR^(e0))R^(b0), OS(O)₂R^(b0), SF₅, P(O)R^(f0)R^(g0),OP(O)(OR^(h0))(OR^(i0)), P(O)(OR^(h0))(OR^(i0)), and BR^(j0)R^(k0),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents; each R^(a0), R^(c0), andR^(d0) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(S) substituents; or, any R^(c0) and R^(d0) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(S) substituents; each R^(b0) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(S) substituents; each R^(e0) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl; each R^(f0) and R^(g0) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;each R^(h0) and R^(i0) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;each R^(j0) and R^(k0) is independently selected from OH, C₁₋₆alkoxy,and C₁₋₆ haloalkoxy; or any R^(j0) and R^(k0) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; Ring moiety A is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; Ringmoiety B is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl; Ring C is selected froma phenyl ring, a 5-6 membered heteroaryl ring, a C₃₋₇ cycloalkyl ring,and a 5-7 membered heterocycloalkyl ring; each R^(A) and R^(B) isindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a9), SR^(a9), NHOR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9),C(O)NR^(c9)(OR^(a9)), C(O)OR^(a9), OC(O)R^(b9), OC(O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), C(═NR^(e9))R^(b9),C(═NR^(e9))NR^(c9)R^(d9), NR^(c9)C(═NR^(e9))NR^(c9)R^(d9),NR^(c9)C(═NR^(e9))R^(b9), NR^(c9)S(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)(═NR^(e9))R^(b9),NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9), S(O)NR^(c9)R^(d9), S(O)₂R^(b9),S(O)₂NR^(c9)R^(d9), OS(O)(═NR^(e9))R^(b9), OS(O)₂R^(b9), SF₅,P(O)R^(f9)R^(g9), OP(O)(OR^(h9))(OR^(i9)), P(O)(OR^(h9))(OR^(i9)), andBR^(j9)R^(k9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(9A) substituents; each R^(a9), R^(c9), andR^(d9) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(9A) substituents; or, any R^(c9) and R^(d9) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(9A) substituents; each R^(b9) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(9A) substituents; each R^(e9) is independently selected fromH, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl; each R^(f9) and R^(g9) areindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;each R^(h9) and R^(i9) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl;each R^(j9) and R^(k9) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j9) and R^(k9) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; each R^(9A) is independently selected from H, D, halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a91), SR^(a91), NHOR^(a91), C(O)R^(b91), C(O)NR^(c91)R^(d91),C(O)NR^(c91)(OR^(a91)), C(O)OR^(a91), OC(O)R^(b91),OC(O)NR^(c91)R^(d91), NR^(c91)R^(d91), NR^(c91)NR^(c91)R^(d91),NR^(c91)C(O)R^(b91), NR^(c91)C(O)OR^(a91), NR^(c91)C(O)NR^(c91)R^(d91),C(═NR^(e91))R^(b91), C(═NR^(e91))NR^(c91)R^(d91),NR^(c91)C(═NR^(e91))NR^(c91)R^(d91), NR^(c91)C(═NR^(e91))R^(b91),NR^(c91)S(O)NR^(c91)R^(d91), NR^(c91)S(O)R^(b91), NR^(c91)S(O)₂R^(b91),NR^(c91)S(O)(═NR^(e91))R^(b91), NR^(c91)S(O)₂NR^(c91)R^(d91),S(O)R^(b91), S(O)NR^(c91)R^(d91), S(O)₂R^(b91), S(O)₂NR^(c91)R^(d91),OS(O)(═NR^(e91))R^(b91), OS(O)₂R^(b91), SF₅, P(O)R^(ol)R^(g91),0P(O)(OR^(h91))(OR^(i91)), P(O)(OR^(h91))(OR^(i91)), andBR^(j91)R^(k91), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents; each R^(a91), R^(c91), andR^(d91) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(S) substituents; or, any R^(c91)and R^(d91) attached to the same N atom, together with the N atom towhich they are attached, form a 5- or 6-membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5- or 6-membered heteroarylor 4-7 membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(S) substituents; each R^(b91) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, which are each optionally substituted with 1, 2,3, or 4 independently selected R^(S) substituents; each R^(e91) isindependently selected from H, OH, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(f91) and R^(g91) are independently selected from H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl; each R^(h91) and R^(i91) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(j91) and R^(k91) is independently selected from OH, C₁₋₆ alkoxy,and C₁₋₆ haloalkoxy; or any R^(j91) and R^(k91) attached to the same Batom, together with the B atom to which they are attached, form a 5- or6-membered heterocycloalkyl group optionally substituted with 1, 2, 3,or 4 substituents independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl; L¹ is selected from —R—R—, —R—R—R—, -Cy-, —R-Cy-, -Cy-R—,—R-Cy-R—, —R—R-Cy-, -Cy-R—R—, and -Cy-R-Cy-; each R is independentlyselected from M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₁₋₆alkylene-M, M-C₁₋₆ alkylene, C₁₋₆ alkylene-M-C₁₋₆ alkylene, M-C₁₋₆alkylene-M, C₂₋₆ alkenylene-M, M-C₂₋₆ alkenylene, C₂₋₆ alkenylene-M-C₂₋₆alkenylene, M-C₂₋₆ alkenylene-M, C₂₋₆ alkynylene-M, M-C₂₋₆ alkynylene,C₂₋₆ alkynylene-M-C₂₋₆ alkynylene, and M-C₂₋₆ alkynylene-M, wherein eachof said C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected R^(S) substituents; each Cy is independently selected fromC₃₋₁₄ cycloalkyl, phenyl, 4-14 membered heterocycloalkyl, and 5-6membered heteroaryl, each of which is optionally substituted with 1, 2,3, or 4 independently selected R^(S) substituents; each M isindependently selected from —O—, —S—, —C(O)—, —C(O)NR^(L)—, —C(O)O—,—OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂—, —S(O)₂—, —S(O)₂NR^(L)—, and—NR^(L)S(O)₂NR^(L)—; provided that when M is attached to a nitrogenatom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—,and —S(O)₂NR^(L)—; each R^(L) is independently selected from H, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, and C₁₋₃ haloalkyl; and each R^(S) isindependently selected from H, D, OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl,C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino,C₁₋₃ alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Z is N, U is CR^(U),and Y is N.
 3. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Z is N, U is CH, and Y is N.
 4. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R², R³,R⁵, R⁶, R⁷, R⁸, and each R⁴ are each independently selected from H, D,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R², R³, R⁵, R⁶, R⁷, R⁸, and each R⁴ areeach independently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents.
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(a2), R^(c2),and R^(d2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(2A) substituents; and each R^(b2)is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(2A) isindependently selected from H, D, OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl,C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino,C₁₋₃ alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R², R³, R⁵, R⁶, R⁷, R⁸and each R⁴ are each independently selected from H, D, halo, CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, C(O)NH₂, OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy,wherein the C₁₋₆ alkoxy is optionally substituted by HO—C₁₋₃ alkyl orC₁₋₃ alkoxy-C₁₋₃ alkyl.
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is selected from H,D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy, wherein the C₁₋₆ alkoxy is optionally substituted by HO—C₁₋₃alkyl or C₁₋₃ alkoxy-C₁₋₃ alkyl.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is H.
 11. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is selected from C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); and each R^(a2), R^(b2), R^(c2),and R^(d2) is independently selected from H and C₁₋₆ alkyl.
 12. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is C(O)NH₂.
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein r is
 0. 14. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁵ is selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, wherein the C₁₋₆ alkoxy is optionallysubstituted by HO—C₁₋₃ alkyl or C₁₋₃ alkoxy-C₁₋₃ alkyl.
 15. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ isselected from methoxy, 3-hydroxypropoxy, and 3-methoxypropoxy.
 16. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶ is selected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, wherein the C₁₋₆ alkoxy is optionallysubstituted by HO—C₁₋₃ alkyl or C₁₋₃ alkoxy-C₁₋₃ alkyl.
 17. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ isH.
 18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁷ is selected from C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); and each R^(a2),R^(b2), R^(c2), and R^(d2) is independently selected from H and C₁₋₆alkyl.
 19. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁷ is C(O)NH₂.
 20. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁸ is selected from H,D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy, wherein the C₁₋₆ alkoxy is optionally substituted by HO—C₁₋₃alkyl or C₁₋₃ alkoxy-C₁₋₃ alkyl.
 21. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁸ is H.
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Ring moiety A is a 5-6 membered heteroaryl.
 23. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Ringmoiety A is a pyrazole ring.
 24. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein u is 0, 1, or
 2. 25.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(A) is independently selected from H, halo, CN, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.
 26. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR^(A) is independently selected from H and C₁₋₆ alkyl.
 27. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein eachR^(A) is independently selected from H, methyl, and ethyl.
 28. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Ring moiety B is a 5-6 membered heteroaryl.
 29. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Ringmoiety B is a pyrazole ring.
 30. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein v is 0, 1, or
 2. 31.The compound of claim 1, or a pharmaceutically acceptable salt thereof,each R^(B) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.
 32. The compound of claim 1,or a pharmaceutically acceptable salt thereof, each R^(B) isindependently selected from H and C₁₋₆ alkyl.
 33. The compound of claim1, or a pharmaceutically acceptable salt thereof, each R^(B) isindependently selected from H, methyl, and ethyl.
 34. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Ringmoiety C is a 5-6 membered heteroaryl.
 35. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Ring moiety C isfuranyl.
 36. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein L¹ is selected from —R—R— and —R—R—R—.
 37. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R is independently selected from M, C₁₋₆ alkylene, C₂₋₆alkenylene, and C₂₋₆ alkynylene.
 38. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each M isindependently selected from —O—, —C(O)—, —C(O)NR^(L)—, —OC(O)NR^(L)—,—NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂—, —S(O)₂—, and—S(O)₂NR^(L)—, provided that when M is attached to a nitrogen atom, thenM is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—, and—S(O)₂NR^(L)—; and each R^(L) is independently selected from H and C₁₋₃alkyl.
 39. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R is independently selected from C₁₋₃alkylene and C₂₋₃ alkenylene.
 40. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L¹ is —CH₂—CH═CH—CH₂—.41. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: r is 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, or 4; v is 0,1, 2, 3, or 4; R², R³, R⁵, R⁶, R⁷, R⁸ and each R⁴ are each independentlyselected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), and OP(O)(OR^(h2))(OR^(i2)), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; each R^(a2), R^(c2), and R^(d2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; or, any R^(c2) and R^(d2) attached to the same Natom, together with the N atom to which they are attached, form a 5- or6-membered heteroaryl or a 4-7 membered heterocycloalkyl group, whereinthe 5- or 6-membered heteroaryl or 4-7 membered heterocycloalkyl groupis optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; each R^(b2) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents; each R^(h2) and R^(i2) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl;each R^(2A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a21), SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21), NR^(c21)C(O)NR^(c21)R^(d21),NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)₂R^(b21),S(O)₂NR^(c21)R^(d21), and OP(O)(OR^(h21))(OR^(i21)), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents; each R^(a21), R^(c21), and R^(d21) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyland C₁₋₆ haloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents; each R^(b21) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, which areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents; each R^(h21) and R^(i21) is independently selectedfrom H and C₁₋₆ alkyl; each R^(2B) is independently selected from H, D,OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl,carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy,C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino; U is N or CR^(U); Y is N or CR^(Y); Z is N orCR^(Z); wherein (i) Z is CR^(Z), U is CR^(U), and Y is CR^(Y); or (ii) Zis N, U is CR^(U), and Y is CR^(Y); or (iii) Z is CR^(Z), U is N, and Yis CR^(Y); or (iv) Z is CR^(Z), U is CR^(U), and Y is N; or (v) Z is N,U is N, and Y is CR^(Y); or (vi) Z is CR^(Z), U is N, and Y is N; or(vii) Z is N, U is CR^(U), and Y is N; R^(U), R^(Y), and R^(Z) are eachindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a0), SR^(a0), NHOR^(a0),C(O)R^(b0), C(O)NR^(c0)R^(d0), C(O)NR^(c0)(OR^(a0)), C(O)OR^(a0),OC(O)R^(b0), OC(O)NR^(c0)R^(d0), NR^(c0)R^(d0), NR^(c0)NR^(c0)R^(d0),NR^(c0)C(O)R^(b0), NR^(c0)C(O)OR^(a0), NR^(c0)C(O)NR^(c0)R^(d0),NR^(c0)S(O)₂R^(b0), NR^(c0)S(O)₂NR^(c0)R^(d0), S(O)₂R^(b0),S(O)₂NR^(c0)R^(d0), and OP(O)(OR^(h0))(OR^(i0)), wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents; each R^(a0), R^(c0), and R^(d0) is independently selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl and C₁₋₆haloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(S) substituents; each R^(b0) is independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, which are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(S)substituents; each R^(h0) and R^(i0) is independently selected from Hand C₁₋₆ alkyl; Ring moiety A is selected from C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl; Ring moietyB is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl; Ring C is selected from aphenyl ring, a 5-6 membered heteroaryl ring, a C₃₋₇ cycloalkyl ring, anda 5-7 membered heterocycloalkyl ring; each R^(A) and R^(B) isindependently selected from H, halo, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl; L¹ is selected from —R—R—, —R—R—R—, -Cy-,—R-Cy-, -Cy-R—, and —R-Cy-R—; each R is independently selected from M,C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₁₋₆ alkylene-M, andM-C₁₋₆ alkylene, wherein each of said C₁₋₆ alkylene, C₂₋₆ alkenylene,and C₂₋₆ alkynylene is optionally substituted with 1, 2, 3, or 4substituents independently selected R^(S) substituents; each Cy isindependently selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(S)substituents; each M is independently selected from —O—, —C(O)—,—C(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂—,—S(O)₂—, and —S(O)₂NR^(L)—, provided that when M is attached to anitrogen atom, then M is selected from —C(O)—, —C(O)NR^(L)—, —S(O)₂—,and —S(O)₂NR^(L)—; each R^(L) is independently selected from H and C₁₋₃alkyl; and each R^(S) is independently selected from H, D, OH, NO₂, CN,halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl,C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino,C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.
 42. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: r is 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, or 4; v is 0, 1, 2, 3,or 4; R², R³, R⁵, R⁶, R⁷, R⁸, and each R⁴ are each independentlyselected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents; each R^(a2),R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents; or, any R^(c2)and R^(d2) attached to the same N atom, together with the N atom towhich they are attached, form a 5- or 6-membered heteroaryl or a 4-7membered heterocycloalkyl group, wherein the 5- or 6-membered heteroarylor 4-7 membered heterocycloalkyl group is optionally substituted with 1,2, 3, or 4 independently selected R^(2A) substituents; each R^(b2) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, which are each optionally substituted with 1, 2,3, or 4 independently selected R^(2A) substituents; each R^(2A) isindependently selected from H, D, OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl,C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino,C₁₋₃ alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino; U is CR^(U); Y is N; Z is N; R^(U) is selectedfrom H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, C₁₋₃ alkyl, C₁₋₃haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, and C₁₋₃ alkoxycarbonyl;Ring moiety A is 5-6 membered heteroaryl; Ring moiety B is 5-6 memberedheteroaryl; Ring C is a 5-6 membered heteroaryl ring; each R^(A) andR^(B) is independently selected from H, halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl; L¹ is selected from —R—R— and —R—R—R—; each R isindependently selected from M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, and M-C₁₋₆ alkylene, wherein each of saidC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted with 1, 2, 3, or 4 substituents independently selected R^(S)substituents; each M is independently selected from —O—, —C(O)—,—C(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂—,—S(O)₂—, and —S(O)₂NR^(L)—, provided that when M is attached to anitrogen atom, then M is selected from —C(O)—, —C(O)NR^(L)—, —S(O)₂—,and —S(O)₂NR^(L)—; each R^(L) is independently selected from H and C₁₋₃alkyl; and each R^(S) is independently selected from H, D, OH, NO₂, CN,halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl,C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino,C₁₋₃ alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.
 43. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: r is 0, 1, or 2; u is 0, 1, or 2; v is 0, 1, or 2; R², R³, R⁵,R⁶, R⁷, R⁸ and each R⁴ are each independently selected from H, halo, CN,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents; each R^(a2), R^(c2), andR^(d2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(2A) substituents; each R^(b2) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,which are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents; each R^(2A) is independently selected fromH, D, OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl,carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy,C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino; U is CR^(U); Y is N; Z is N; R^(U) is selectedfrom H, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; Ring moiety A is5-membered heteroaryl; Ring moiety B is 5-membered heteroaryl; Ring C isa 5-membered heteroaryl ring; each R^(A) and R^(B) is independentlyselected from H and C₁₋₆ alkyl; L¹ is selected from —R—R— and —R—R—R—;each R is independently selected from C₁₋₆ alkylene, C₂₋₆ alkenylene,and C₂₋₆ alkynylene, wherein each of said C₁₋₆ alkylene, C₂₋₆alkenylene, and C₂₋₆ alkynylene is optionally substituted with 1, 2, 3,or 4 substituents independently selected R^(S) substituents; and eachR^(S) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃alkoxycarbonylamino, C₁₋₃ alkylaminocarbonyloxy, C₁₋₃alkylsulfonylamino, aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃alkyl)aminosulfonyl, aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino,di(C₁₋₃ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.
 44. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: r is 0, 1, or 2; u is 0, 1, or 2; v is 0, 1, or 2; R², R³, R⁵,R⁶, R⁷, R⁸, and each R⁴ are each independently selected from H, halo,CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a2), and C(O)NR^(c2)R^(d2), whereinsaid C₁₋₆ alkyl and C₁₋₆ haloalkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents; each R^(a2),R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(2A) substituents; each R^(2A) isindependently selected from H, D, OH, NO₂, CN, halo, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃alkyl)amino, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, anddi(C₁₋₃ alkyl)carbamyl; U is CR^(U); Y is N; Z is N; R^(U) is H; Ringmoiety A is a pyrazole ring; Ring moiety B is a pyrazole ring; Ring C isfuranyl; each R^(A) and R^(B) is independently selected from H and C₁₋₆alkyl; L¹ is selected from —R—R— and —R—R—R—; and each R isindependently selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆alkynylene.
 45. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: r is 0, 1, or 2; u is 0, 1, or 2; v is0, 1, or 2; R², R⁵, R⁶, R⁸, and each R⁴ are each independently selectedfrom H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy, wherein the C₁₋₆ alkoxy is optionally substituted by HO—C₁₋₃alkyl or C₁₋₃ alkoxy-C₁₋₃ alkyl; R³ and R⁷ are each independentlyselected from OR^(a2), SR³², C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); each R^(a2), R^(b2), R^(c2), andR^(d2) is independently selected from H and C₁₋₆ alkyl U is CR^(U); Y isN; Z is N; R^(U) is H; Ring moiety A is a pyrazole ring; Ring moiety Bis a pyrazole ring; Ring C is furanyl; each R^(A) and R^(B) isindependently selected from H and C₁₋₆ alkyl; L¹ is selected from —R—R—and —R—R—R—; and each R is independently selected from C₁₋₆ alkylene,C₂₋₆ alkenylene, and C₂₋₆ alkynylene.
 46. The compound of claim 1,having Formula (Ic):

or a pharmaceutically acceptable salt thereof.
 47. The compound of claim1, having Formula (Id):

or a pharmaceutically acceptable salt thereof.
 48. The compound of claim1, selected from:(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide;(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide;and(E)-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzofuro[6,7-d]imidazole-5-carboxamide,or a pharmaceutically acceptable salt thereof.
 49. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 50.(canceled)
 51. (canceled)
 52. A method of treating a STING-mediateddisease or disorder comprising administering a therapeutically effectiveamount of a compound of claim 1, or pharmaceutically acceptable saltthereof, to a human in need thereof.
 53. The method of claim 52, whereinthe disease or disorder is cancer.
 54. The method of claim 52, whereinthe disease or disorder is an infectious disease.
 55. The method ofclaim 52, wherein the disease or disorder is sickle cell disease orsickle cell anemia.